U.S. patent application number 11/957091 was filed with the patent office on 2009-03-05 for 3-h-pyrazolopyridines and salts thereof, pharmaceutical compositions comprising same, methods of preparing same and uses of same..
Invention is credited to Ulf Boemer, Ingo HARTUNG, Georg Kettschau, Ingrid Schumann, Karl Heinz Thierauch.
Application Number | 20090062273 11/957091 |
Document ID | / |
Family ID | 39415078 |
Filed Date | 2009-03-05 |
United States Patent
Application |
20090062273 |
Kind Code |
A1 |
HARTUNG; Ingo ; et
al. |
March 5, 2009 |
3-H-pyrazolopyridines and salts thereof, pharmaceutical
compositions comprising same, methods of preparing same and uses of
same.
Abstract
The invention relates to 3-H-pyrazolopyridines according to the
general formula (I): ##STR00001## in which A, B, D, E, R.sup.a,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and q are as defined in
the claims, and salts, N-oxides, solvates and prodrugs thereof, to
pharmaceutical compositions comprising said 3-H-pyrazolopyridine
compounds, to methods of preparing said 3-H-pyrazolopyridines, to
intermediate compounds useful in said methods, to uses of said
intermediate compounds in the preparation of said
3-H-pyrazolopyridines, as well as to uses of said
3-H-pyrazolopyridines for manufacturing a pharmaceutical
composition for the treatment of diseases of dysregulated vascular
growth or of diseases which are accompanied with dysregulated
vascular growth, wherein the compounds effectively interfere with
Tie2 signalling.
Inventors: |
HARTUNG; Ingo; (Berlin,
DE) ; Kettschau; Georg; (Berlin, DE) ;
Schumann; Ingrid; (Berlin, DE) ; Thierauch; Karl
Heinz; (Berlin, DE) ; Boemer; Ulf;
(Glienicke/Nordbahn, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD., SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
39415078 |
Appl. No.: |
11/957091 |
Filed: |
December 14, 2007 |
Current U.S.
Class: |
514/234.2 ;
514/253.04; 514/303; 544/127; 544/362; 546/119 |
Current CPC
Class: |
A61P 13/08 20180101;
A61P 17/02 20180101; C07D 471/04 20130101; A61P 17/00 20180101;
A61P 9/12 20180101; A61P 37/08 20180101; A61P 19/08 20180101; A61P
25/00 20180101; A61P 29/00 20180101; A61P 9/10 20180101; A61P 11/06
20180101; A61P 27/02 20180101; A61P 17/06 20180101; A61P 35/00
20180101; A61P 15/00 20180101; A61P 1/16 20180101; A61P 35/02
20180101; A61P 11/00 20180101; A61P 35/04 20180101; A61P 9/00
20180101; A61P 19/02 20180101 |
Class at
Publication: |
514/234.2 ;
546/119; 544/127; 514/303; 514/253.04; 544/362 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 471/04 20060101 C07D471/04; A61K 31/496 20060101
A61K031/496; A61K 31/437 20060101 A61K031/437 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 15, 2006 |
EP |
06090224.4 |
Sep 19, 2007 |
EP |
07075832.1 |
Claims
1. A compound of general formula (I): ##STR00225## in which:
represents H or --C(O)R.sup.b, or is selected from the group
comprising, preferably consisting of, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
wherein said residues are unsubstituted or substituted one or more
times, independently from each other, with R.sup.6; R.sup.2
represents hydrogen, halogen, --NR.sup.d1R.sup.d2, --OR.sup.c,
--C(O)R.sup.b, or is selected from the group comprising, preferably
consisting of, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, heteroaryl, wherein said
residues are unsubstituted or one or more times substituted
independently from each other with R.sup.7; R.sup.3 is selected
from the group comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, hydroxy,
amino, halogen, and cyano; R.sup.4, R.sup.5, R.sup.6, R.sup.7
independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2,
wherein C.sub.1-C.sub.6-alkyl, aryl, heteroaryl,
C.sub.3-C.sub.10-heterocycloalkyl and C.sub.3-C.sub.10-cycloalkyl
are optionally substituted one or more times by R.sup.8; R.sup.8 is
selected from the group comprising, preferably consisting of,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2;
R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and C.sub.1-C.sub.6-alkyl; R.sup.b is
selected from the group comprising, preferably consisting of,
hydroxyl, --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2,
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with hydroxyl, halogen, or
C.sub.1-C.sub.6-alkoxy; R.sup.c is selected from the group
comprising, preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
aryl, --OR.sup.f, --NR.sup.d1R.sup.d2, or --OP(O)(OR.sup.f).sub.2;
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl are optionally substituted one or more times,
the same way or differently with halogen, hydroxy or the group
aryl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; or R.sup.d1 and
R.sup.d2 together with the nitrogen atom to which they are
attached, form a 3 to 10 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, halogen,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted one or more times, the same way or differently, by a
member of the group comprising, preferably consisting of, NH,
NR.sup.d3, oxygen or sulphur, and can optionally be interrupted one
or more times, the same way or differently, with a --C(O)--,
--S(O)--, and/or --S(O).sub.2-- group, and can optionally contain
one or more double bonds R.sup.d3 is selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, hydroxyl,
halogen, C.sub.1-C.sub.6-haloalkyl or C.sub.1-C.sub.6-alkoxy;
R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and
heteroaryl; R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1,
R.sup.g2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl; R.sup.g1
and R.sup.g2 together with the nitrogen atom to which they are
attached, form a 3 to 10 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted one or more
times, the same way or differently, by a member of the group
comprising, preferably consisting of, NH, NR.sup.a, oxygen or
sulphur, and can optionally be interrupted one or more times, the
same way or differently, with a --C(O)--, --S(O)--, and/or
--S(O).sub.2-- group, and can optionally contain one or more double
bonds; A is selected from the group comprising, preferably
consisting of, --C(O)--, --C(S)--, --C(.dbd.NR.sup.a)--,
--C(O)NR.sup.a--, --C(.dbd.NR.sup.a)NR.sup.a--, --S(O).sub.2--,
--S(O)(.dbd.NR.sup.a)--, --S(.dbd.NR.sup.a).sub.2--,
--C(S)NR.sup.a--, --C(O)C(O)--, --C(O)C(O)NR.sup.a--,
--C(O)NR.sup.aC(O)--, --C(S)NR.sup.aC(O)--, and
--C(O)NR.sup.aC(S)--; B is a bond or selected from the group
comprising, preferably consisting of C.sub.1-C.sub.6-alkylene,
C.sub.3-C.sub.10-cycloalkylene, and
C.sub.3-C.sub.10-heterocycloalkylene; D, E are, independently from
each other, arylene or heteroarylene; and q represents an integer
of 0, 1, or 2 or a salt, an N-oxide, a solvate or a prodrug
thereof, wherein, when one or more of R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 is (are) present in one position in the molecule as well
as in one or more further positions in the molecule, said R.sup.a,
R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f,
R.sup.g1, R.sup.g2, or R.sup.8 has (have), independently from each
other, the same meanings as defined above in said first position in
the molecule and in said second or further positions in the
molecule, it being possible for the two or more occurrences of
R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e,
R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 within a single molecule to
be identical or different.
2. The compound according to claim 1, wherein: R.sup.1 represents H
or --C(O)R.sup.b, or is selected from the group comprising,
preferably consisting of, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.10-cycloalkyl, and C.sub.3-C.sub.10-heterocycloalkyl,
wherein said residues are unsubstituted or substituted one or more
times, independently from each other, with R.sup.6; R.sup.2
represents hydrogen, halogen, --NR.sup.d1R.sup.d2, --OR.sup.c, or
--C(O)R.sup.b, or is selected from the group comprising, preferably
consisting of, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein
said residues are unsubstituted or one or more times substituted
independently from each other with R.sup.7; R.sup.3 is selected
from the group comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, hydroxy,
amino, halogen, and cyano; R.sup.4, R.sup.5, R.sup.6, R.sup.7
independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2,
wherein C.sub.1-C.sub.6-alkyl, aryl, heteroaryl,
C.sub.3-C.sub.10-heterocycloalkyl and C.sub.3-C.sub.10-cycloalkyl
are optionally substituted one or more times by R.sup.8; R.sup.8 is
selected from the group comprising, preferably consisting of,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2;
R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and C.sub.1-C.sub.6-alkyl; R.sup.b is
selected from the group comprising, preferably consisting of,
hydroxyl, --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2,
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with hydroxyl, halogen, or
C.sub.1-C.sub.6-alkoxy; R.sup.c is selected from the group
comprising, preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
aryl, --OR.sup.f, --NR.sup.d1R.sup.d2, or --OP(O)(OR.sup.f).sub.2;
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl are optionally substituted one or more times,
the same way or differently with halogen, hydroxy or the group
aryl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e--OP(O)(OR.sup.f).sub.2; or R.sup.d1 and
R.sup.d2 together with the nitrogen atom to which they are
attached, form a 3 to 10 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, halogen,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted one or more times, the same way or differently, by a
member of the group comprising, preferably consisting of, NH,
NR.sup.d3, oxygen or sulphur, and can optionally be interrupted one
or more times, the same way or differently, with a --C(O)--,
--S(O)--, and/or --S(O).sub.2-- group, and can optionally contain
one or more double bonds R.sup.d3 is selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, hydroxyl,
halogen, C.sub.1-C.sub.6-haloalkyl or C.sub.1-C.sub.6-alkoxy;
R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and
heteroaryl; R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1,
R.sup.g2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl; R.sup.g1
and R.sup.g2 together with the nitrogen atom to which they are
attached, form a 3 to 10 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted one or more
times, the same way or differently, by a member of the group
comprising, preferably consisting of, NH, NR.sup.a, oxygen or
sulphur, and can optionally be interrupted one or more times, the
same way or differently, with a --C(O)--, --S(O)--, and/or
--S(O).sub.2-- group, and can optionally contain one or more double
bonds; A represents --C(O)-- or --C(O)NR.sup.a--; B is a bond or
selected from the group comprising, preferably consisting of
C.sub.1-C.sub.3-alkylene and C.sub.3-C.sub.5-cycloalkylene; D, E
are, independently from each other, arylene or heteroarylene; and q
represents an integer of 0, or 1; wherein, when one or more of
R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e,
R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are) present in one
position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different.
3. The compound according to claim 1, wherein: R.sup.1 represents
H, C.sub.1-C.sub.6-alkyl, or C.sub.2-C.sub.6-alkenyl, wherein
C.sub.1-C.sub.6-alkyl is unsubstituted or substituted one or more
times, independently from each other, with R.sup.6; R.sup.2
represents hydrogen, halogen, --NR.sup.d1R.sup.d2, --OR.sup.c,
--C(O)R.sup.b, or C.sub.1-C.sub.6-alkyl, wherein
C.sub.1-C.sub.6-alkyl is unsubstituted or one or more times
substituted independently from each other with R.sup.7; R.sup.3 is
selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, and cyano; R.sup.4, R.sup.5, R.sup.6, R.sup.7
independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
aryl, heteroaryl, C.sub.3-C.sub.6-heterocycloalkyl and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times by R.sup.8; R.sup.8 is selected from the group comprising,
preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.a
is selected from the group comprising, preferably consisting of,
hydrogen and methyl R.sup.b is selected from the group comprising,
preferably consisting of, hydroxyl, --OR.sup.c, --SR.sup.c,
--NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; R.sup.c is
selected from the group comprising, preferably consisting of,
hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times with
hydroxyl, halogen, aryl, --OR.sup.f, or --NR.sup.d1R.sup.d2;
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times, the
same way or differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or R.sup.d1 and R.sup.d2 together with the
nitrogen atom to which they are attached, form a 3 to 7 membered
heterocycloalkyl ring, which is optionally substituted one or more
times, the same way or differently, with C.sub.1-C.sub.4-alkyl,
halogen, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e, or
--S(O).sub.2R.sup.e; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted one or more
times, the same way or differently, by a member of the group
comprising, preferably consisting of, NH, NR.sup.d3, or oxygen, and
can optionally be interrupted one or more times, the same way or
differently, with a --C(O)-- group; R.sup.d3 is selected from the
group comprising, preferably consisting of hydrogen and
C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is optionally
substituted one or more times with C.sub.3-C.sub.6-cycloalkyl,
hydroxyl, halogen, C.sub.1-C.sub.4-haloalkyl or
C.sub.1-C.sub.4-alkoxy; R.sup.e is selected from the group
comprising, preferably consisting of, --NR.sup.g1R.sup.g2,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.3-alkoxy, aryl and heteroaryl; R.sup.f is selected
from the group comprising, preferably consisting of, hydrogen,
--C(O)R.sup.e, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.2; R.sup.g1,
R.sup.g2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; R.sup.g1
and R.sup.g2 together with the nitrogen atom to which they are
attached, form a 3 to 6 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted one or more
times, the same way or differently, by a member of the group
comprising, preferably consisting of, NH, NR.sup.a, or oxygen; A
represents --C(O)NR.sup.a--; B is a bond; D, E are, independently
from each other, arylene or heteroarylene; and q is 0; wherein,
when one or more of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2,
R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are)
present in one position in the molecule as well as in one or more
further positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different.
4. The compound according to claim 1, wherein: R.sup.1 represents
H, C.sub.1-C.sub.6-alkyl, or C.sub.2-C.sub.6-alkenyl, wherein
C.sub.1-C.sub.6-alkyl is unsubstituted or substituted one or more
times, independently from each other, with R.sup.6; R.sup.2
represents hydrogen, halogen, --NR.sup.d1R.sup.d2, --OR.sup.c,
--C(O)R.sup.b, or C.sub.1-C.sub.6-alkyl, wherein
C.sub.1-C.sub.6-alkyl is unsubstituted or one or more times
substituted independently from each other with R.sup.7; R.sup.3 is
selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, and cyano; R.sup.4, R.sup.5, R.sup.6, R.sup.7
independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
aryl, heteroaryl, C.sub.3-C.sub.6-heterocycloalkyl and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times by R.sup.8; R.sup.8 is selected from the group comprising,
preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.a
is selected from the group comprising, preferably consisting of,
hydrogen and methyl; R.sup.b is selected from the group comprising,
preferably consisting of, hydroxyl, --OR.sup.c, --SR.sup.c,
--NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; R.sup.c is
selected from the group comprising, preferably consisting of,
hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times with
hydroxyl, halogen, aryl, --OR.sup.f, or --NR.sup.d1R.sup.d2;
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times, the
same way or differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or R.sup.d1 and R.sup.d2 together with the
nitrogen atom to which they are attached, form a 3 to 7 membered
heterocycloalkyl ring, which is optionally substituted one or more
times, the same way or differently, with C.sub.1-C.sub.4-alkyl,
halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; R.sup.d3 represents
hydrogen or C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is
optionally substituted once by a C.sub.3-C.sub.6-cycloalkyl,
hydroxyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or
halogen; R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1,
R.sup.g2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; R.sup.g1
and R.sup.g2 together with the nitrogen atom to which they are
attached, form a 3 to 6 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted once by a
member of the group comprising, preferably consisting of, NH,
NR.sup.a, or oxygen; A represents --C(O)NR.sup.a--; B is a bond; D
is para-phenylene; E is phenylene or heteroarylene and q is 0;
wherein, when one or more of R.sup.a, R.sup.b, R.sup.c, R.sup.d1,
R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or
R.sup.8 is (are) present in one position in the molecule as well as
in one or more further positions in the molecule, said R.sup.a,
R.sup.b, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 has (have), independently from each other, the
same meanings as defined above in said first position in the
molecule and in said second or further positions in the molecule,
it being possible for the two or more occurrences of R.sup.a,
R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f,
R.sup.g1, R.sup.g2, or R.sup.8 within a single molecule to be
identical or different.
5. The compound according to claim 1, wherein: R.sup.1 represents
H, C.sub.1-C.sub.6-alkyl, or C.sub.2-C.sub.6-alkenyl, wherein
C.sub.1-C.sub.6-alkyl is unsubstituted or substituted one or more
times, independently from each other, with R.sup.6; R.sup.2
represents hydrogen, halogen, --NR.sup.d1R.sup.d2, --OR.sup.c,
--C(O)R.sup.b, or C.sub.1-C.sub.6-alkyl, wherein
C.sub.1-C.sub.6-alkyl is unsubstituted or one or more times
substituted independently from each other with R.sup.7; R.sup.3 is
selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, and cyano; R.sup.4, R.sup.5, R.sup.6, R.sup.7
independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
aryl, heteroaryl, C.sub.3-C.sub.6-heterocycloalkyl and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times by R.sup.8; R.sup.8 is selected from the group comprising,
preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.a
is selected from the group comprising, preferably consisting of,
hydrogen and methyl R.sup.b is selected from the group comprising,
preferably consisting of, hydroxyl, --OR.sup.c, --SR.sup.c,
--NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; R.sup.c is
selected from the group comprising, preferably consisting of,
hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times with
hydroxyl, halogen, aryl, --OR.sup.f, or --NR.sup.d1R.sup.d2;
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times, the
same way or differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or R.sup.d1 and R.sup.d2 together with the
nitrogen atom to which they are attached, form a 3 to 7 membered
heterocycloalkyl ring, which is optionally substituted one or more
times, the same way or differently, with C.sub.1-C.sub.4-alkyl,
halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; R.sup.d3 represents
hydrogen or C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is
optionally substituted once by a C.sub.3-C.sub.6-cycloalkyl,
hydroxyl, C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or
halogen; R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1,
R.sup.g2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; R.sup.g1
and R.sup.g2 together with the nitrogen atom to which they are
attached, form a 3 to 6 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted once by a
member of the group comprising, preferably consisting of, NH,
NR.sup.a, or oxygen; A represents --C(O)NR.sup.a--; B is a bond; D
is para-phenylene; E is heteroarylene and q is 0; wherein, when one
or more of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3,
R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are) present
in one position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different.
6. The compound according to claim 1, wherein: R.sup.1 represents H
or C.sub.1-C.sub.4-alkyl wherein C.sub.1-C.sub.4-alkyl is
unsubstituted or substituted one or more times with R.sup.6;
R.sup.2 represents hydrogen; R.sup.3 is selected from the group
comprising, preferably consisting of, hydrogen, methyl, methoxy,
fluorine and hydroxy; R.sup.4 is selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-cycloalkyl, wherein
C.sub.1-C.sub.4-alkyl is optionally substituted by R.sup.8; R.sup.5
is selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.5-C.sub.6-heterocycloalkyl,
C.sub.5-C.sub.6-cycloalkyl, phenyl and pyridyl, wherein
C.sub.1-C.sub.4-alkyl, C.sub.5-C.sub.6-heterocycloalkyl,
C.sub.5-C.sub.6-cycloalkyl, phenyl and pyridyl are optionally
substituted one or more times, independently from each other, with
R.sup.8; R.sup.6, represents hydroxy; R.sup.8 is selected from the
group comprising, preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.a represents hydrogen or
methyl; R.sup.b is selected from the group comprising, preferably
consisting of, hydroxy, --OR.sup.c, --NR.sup.d1R.sup.d2,
C.sub.1-C.sub.3-alkyl, and C.sub.3-C.sub.6-cycloalkyl, R.sup.c
represents C.sub.1-C.sub.3-alkyl or
C.sub.6-C.sub.7-heterocycloalkyl; R.sup.d1, R.sup.d2 independently
from each other are selected from the group comprising, preferably
consisting of hydrogen, and C.sub.1-C.sub.3-alkyl, or R.sup.d1 and
R.sup.d2 together with the nitrogen atom to which they are
attached, form a 3 to 7 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, halogen,
--NR.sup.g1R.sup.g2, or --OR.sup.f; whereby the carbon backbone of
this heterocycloalkyl ring can optionally be interrupted once by a
member of the group comprising, preferably consisting of, NH,
NR.sup.d3, or oxygen; R.sup.d3 represents hydrogen or
C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is optionally
substituted once by a C.sub.3-C.sub.6-cycloalkyl, hydroxy,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or halogen;
R.sup.g1, R.sup.g2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl and C.sub.3-C.sub.6-cycloalkyl; A represents
--C(O)NR.sup.a-- B is a bond; D is a para-phenylene E is a
pyrazole; and q is 0; wherein, when one or more of R.sup.a,
R.sup.c, or R.sup.d3 is (are) present in one position in the
molecule as well as in one or more further positions in the
molecule, said R.sup.a, R.sup.c, or R.sup.d3 has (have),
independently from each other, the same meanings as defined above
in said first position in the molecule and in said second or
further positions in the molecule, it being possible for the two or
more occurrences of R.sup.a, R.sup.c, or R.sup.d3 within a single
molecule to be identical or different.
7. The compound according to claim 1, wherein: R.sup.1 represents
H, or C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; R.sup.2 represents hydrogen, halogen,
--NR.sup.d1R.sup.d2, --OR.sup.c, --C(O)R.sup.b, or
C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or one or more times substituted independently from
each other with R.sup.7; R.sup.3 is selected from the group
comprising, preferably consisting of, hydrogen, methyl, methoxy,
hydroxy, halogen, and cyano; R.sup.4, R.sup.5 independently from
each other, are selected from the group comprising, preferably
consisting of, hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-heterocycloalkyl and C.sub.3-C.sub.6-cycloalkyl are
optionally substituted one or more times by R.sup.8; R.sup.6
independently from each other, are selected from the group
comprising, preferably consisting of, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, hydroxy, halogen, cyano,
--C(O)R.sup.b, --S(O).sub.2R.sup.b, --OR.sup.c, and
--NR.sup.d1R.sup.d2; R.sup.7 independently from each other, are
selected from the group comprising, preferably consisting of,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl,
hydroxy, halogen, cyano, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.8 is selected from the
group comprising, preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.a
is selected from the group comprising, preferably consisting of,
hydrogen and methyl; R.sup.b is selected from the group comprising,
preferably consisting of, hydroxyl, --OR.sup.c,
--NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; R.sup.c is
selected from the group comprising, preferably consisting of,
hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.7-heterocycloalkyl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl are optionally substituted one or
more times with hydroxyl, halogen, aryl, --OR.sup.f, or
--NR.sup.d1R.sup.d2; R.sup.d1, R.sup.d2 independently from each
other are selected from the group comprising, preferably consisting
of hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.6-heterocycloalkyl, or for a group --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --C(O)NR.sup.g1R.sup.g2 wherein
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times, the same way or
differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or R.sup.d1 and R.sup.d2 together with the
nitrogen atom to which they are attached, form a 3 to 7 membered
heterocycloalkyl ring, which is optionally substituted one or more
times, the same way or differently, with C.sub.1-C.sub.4-alkyl,
halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; R.sup.d3 represents
hydrogen or C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is
optionally substituted once by a C.sub.3-cycloalkyl, hydroxyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or halogen;
R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1,
R.sup.g2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; R.sup.g1
and R.sup.g2 together with the nitrogen atom to which they are
attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the
carbon backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; A represents
--C(O)NR.sup.a--; B is a bond; D is para-phenylene; E is phenylene;
and q is 0; wherein, when one or more of R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 is (are) present in one position in the molecule as well
as in one or more further positions in the molecule, said R.sup.a,
R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f,
R.sup.g1, R.sup.g2, or R.sup.8 has (have), independently from each
other, the same meanings as defined above in said first position in
the molecule and in said second or further positions in the
molecule, it being possible for the two or more occurrences of
R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e,
R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 within a single molecule to
be identical or different.
8. The compound according to claim 1, wherein: R.sup.1 represents
H, or C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; R.sup.2 represents hydrogen; R.sup.3 is
selected from the group comprising, preferably consisting of,
hydrogen, methyl, methoxy, hydroxy, and halogen; R.sup.4, R.sup.5
independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, hydroxy, amino, halogen, cyano, nitro,
--C(O)R.sup.b, --S(O).sub.2R.sup.b, --OR.sup.c, and
--NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-heterocycloalkyl and C.sub.3-C.sub.6-cycloalkyl are
optionally substituted one or more times by R.sup.8; R.sup.6
independently from each other, are selected from the group
comprising, preferably consisting of, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, hydroxy, halogen, cyano,
--C(O)R.sup.b, --S(O).sub.2R.sup.b, --OR.sup.c, and
--NR.sup.d1R.sup.d2; R.sup.8 is selected from the group comprising,
preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.a
is selected from the group comprising, preferably consisting of,
hydrogen and methyl; R.sup.b is selected from the group comprising,
preferably consisting of, hydroxyl, --OR.sup.c,
--NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; R.sup.c is
selected from the group comprising, preferably consisting of,
hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.7-heterocycloalkyl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.6-heterocycloalkyl are optionally substituted one or
more times with hydroxyl, halogen, aryl, --OR.sup.f, or
--NR.sup.d1R.sup.d2; R.sup.d1, R.sup.d2 independently from each
other are selected from the group comprising, preferably consisting
of hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.6-heterocycloalkyl, or for a group --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --C(O)NR.sup.g1R.sup.g2 wherein
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.6-heterocycloalkyl are optionally substituted one or
more times, the same way or differently with halogen, hydroxy or
the group --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or R.sup.d1 and R.sup.d2 together with the
nitrogen atom to which they are attached, form a 3 to 7 membered
heterocycloalkyl ring, which is optionally substituted one or more
times, the same way or differently, with C.sub.1-C.sub.4-alkyl,
halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; R.sup.d3 represents
hydrogen or C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is
optionally substituted once by a C.sub.3-cycloalkyl, hydroxyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or halogen;
R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; R.sup.g1,
R.sup.g2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; R.sup.g1
and R.sup.g2 together with the nitrogen atom to which they are
attached, form a 3 to 6 membered heterocycloalkyl ring, whereby the
carbon backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; A represents
C(O)NR.sup.a--; B is a bond; D is para-phenylene; E is phenylene;
and q is 0; wherein, when one or more of R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 is (are) present in one position in the molecule as well
as in one or more further positions in the molecule, said R.sup.a,
R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f,
R.sup.g1, R.sup.g2, or R.sup.8 has (have), independently from each
other, the same meanings as defined above in said first position in
the molecule and in said second or further positions in the
molecule, it being possible for the two or more occurrences of
R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e,
R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 within a single molecule to
be identical or different.
9. The compound according to claim 1, wherein: R.sup.1 represents
H, or C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; R.sup.2 represents hydrogen; R.sup.3 is
selected from the group comprising, preferably consisting of,
hydrogen, methyl, methoxy, hydroxy, and halogen; R.sup.4, R.sup.5
independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, hydroxy, amino, halogen, cyano, nitro,
--C(O)R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2, wherein
C.sub.1-C.sub.3-alkyl and C.sub.3-C.sub.6-heterocycloalkyl are
optionally substituted one or more times by R.sup.8; R.sup.6,
represents hydroxy; R.sup.8 is selected from the group comprising,
preferably consisting of, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, hydroxy, halogen, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2; R.sup.a is selected from the
group comprising, preferably consisting of, hydrogen and methyl;
R.sup.b is selected from the group comprising, preferably
consisting of, hydroxyl, --OR.sup.c, --NR.sup.d1R.sup.d2,
C.sub.1-C.sub.3-alkyl, and C.sub.3-C.sub.6-cycloalkyl; R.sup.c is
selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl
C.sub.3-C.sub.6-cycloalkyl, and C.sub.3-C.sub.7-heterocycloalkyl;
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.6-heterocycloalkyl, or for a group --C(O)R.sup.e, or
--S(O).sub.2R.sup.e wherein C.sub.1-C.sub.3-alkyl, is optionally
substituted one or more times, the same way or differently with
halogen, hydroxy or C.sub.1-C.sub.3-alkoxy; R.sup.d1 and R.sup.d2
together with the nitrogen atom to which they are attached, form a
3 to 7 membered heterocycloalkyl ring, which is optionally
substituted one or more times, the same way or differently, with
C.sub.1-C.sub.4-alkyl, halogen, --NR.sup.g1R.sup.g2 or --OR.sup.f;
whereby the carbon backbone of this heterocycloalkyl ring can
optionally be interrupted once by a member of the group comprising,
preferably consisting of, NH, NR.sup.d3, or oxygen; R.sup.d3
represents hydrogen or C.sub.1-C.sub.4-alkyl, wherein
C.sub.1-C.sub.4-alkyl is optionally substituted once by a
C.sub.3-cycloalkyl, hydroxyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy or halogen; R.sup.e represents
C.sub.1-C.sub.3-alkyl or C.sub.3-C.sub.6-cycloalkyl; A represents
C(O)NR.sup.a--; B is a bond; D is para-phenylene; E is phenylene;
and q is 0; wherein, when one or more of R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, or R.sup.8 is (are) present in one
position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, or R.sup.8 has (have), independently
from each other, the same meanings as defined above in said first
position in the molecule and in said second or further positions in
the molecule, it being possible for the two or more occurrences of
R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, or R.sup.8
within a single molecule to be identical or different.
10. The compound according to claim 1, wherein: R.sup.1 represents
H or C.sub.1-C.sub.3-alkyl wherein said C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times with R.sup.6;
R.sup.2 represents hydrogen; R.sup.3 is selected from the group
comprising, preferably consisting of, hydrogen, methyl, fluorine,
hydroxy and methoxy; R.sup.4 is selected from the group comprising,
preferably consisting of, hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, halogen, and --OR.sup.c, wherein
C.sub.1-C.sub.3-alkyl is optionally substituted by R.sup.8; R.sup.5
is selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
halogen, and --OR.sup.c; R.sup.6, represents hydroxy; R.sup.8 is
selected from the group comprising, preferably consisting of,
C.sub.6-heterocycloalkyl, --OR.sup.c, and --NR.sup.d1R.sup.d2;
R.sup.a represents hydrogen or methyl; R.sup.c represents
C.sub.1-C.sub.3-alkyl or C.sub.6-heterocycloalkyl; R.sup.d1,
R.sup.d2 independently from each other are selected from the group
comprising, preferably consisting of hydrogen, and
C.sub.1-C.sub.6-alkyl, or R.sup.d1 and R.sup.d2 together with the
nitrogen atom to which they are attached, form a 6 membered
heterocycloalkyl ring, whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted by a member of
the group comprising, preferably consisting of, NH, NR.sup.d3, or
oxygen; R.sup.d3 represents hydrogen or methyl; A represents
--C(O)NR.sup.a B is a bond; D is a para-phenylene E is phenylene;
and q is 0; wherein, when one or more of R.sup.a, R.sup.c, or
R.sup.d3 is (are) present in one position in the molecule as well
as in one or more further positions in the molecule, said R.sup.a,
R.sup.c, or R.sup.d3 has (have), independently from each other, the
same meanings as defined above in said first position in the
molecule and in said second or further positions in the molecule,
it being possible for the two or more occurrences of R.sup.a,
R.sup.c, or R.sup.d3 within a single molecule to be identical or
different.
11. The compound according to claim 1 selected from the group
consisting of:
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-phenyl-urea;
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea;
1-(2-Fluoro-5-methyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-y-
l)-phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trifluorometh-
yl-phenyl)-urea;
1-(3-Ethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-
-urea;
1-(3-Ethoxy-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)--
phenyl]-urea;
1-(4-Ethyl-pyridin-2-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-p-
henyl]-urea;
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]p-
yridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trif-
luoromethyl-phenyl)-urea;
1-[2-Methyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trif-
luoromethyl-phenyl)-urea;
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[2-methyl-4-(1-methyl-1H-pyrazolo-
[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Methoxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-tri-
fluoromethyl-phenyl)-urea;
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[2-methoxy-4-(1-methyl-1H-pyrazol-
o[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-Methyl-1-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trif-
luoromethyl-phenyl)-urea;
1-Methyl-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-1-(3-trif-
luoromethyl-phenyl)-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-fluo-
ro-5-trifluoromethyl-phenyl)-urea;
1-[4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(1-me-
thyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Hydroxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-tri-
fluoromethyl-phenyl)-urea;
1-{2-Fluoro-4-[1-(2-hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-{4-[1-(2-hydroxy-ethyl)-1H-pyrazo-
lo[3,4-c]pyridin-4-yl]-phenyl}-urea;
1-{4-[1-(2-Hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3-(3-tr-
ifluoromethyl-phenyl)-urea;
1-(3-Ethyl-phenyl)-3-{2-fluoro-4-[1-(2-hydroxy-ethyl)-1H-pyrazolo[3,4-c]p-
yridin-4-yl]-phenyl}-urea;
1-(4-Ethoxy-pyridin-2-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)--
phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-trifluorometh-
yl-pyridin-2-yl)-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-methyl-3-trif-
luoromethyl-phenyl)-urea;
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea;
1-(2-Chloro-5-methyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-y-
l)-phenyl]-urea;
1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-piperidin-1-y-
l-5-trifluoromethyl-phenyl)-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-piperazin-1-y-
lmethyl-3-trifluoromethyl-phenyl)-urea;
1-{2-Fluoro-4-[1-(2-hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(3-trifluoromethyl-phenyl)-urea;
1-{4-[1-(2-Hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3-[4-(4-
-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea;
1,3-Bis-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trifluoromethy-
l-phenyl)-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-phenyl-urea;
1-(3-Ethoxy-phenyl)-3-[4-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-
-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-fluoro-5-
-methyl-phenyl)-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-fluoro-5-trifl-
uoromethyl-phenyl)-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-m-tolyl-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-methoxy-phenyl-
)-urea;
1-(3-Ethyl-phenyl)-3-[4-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-p-
henyl]-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-(3-trifl-
uoromethyl-phenyl)-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-(2-fluor-
o-5-trifluoromethyl-phenyl)-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-(2-fluor-
o-5-methyl-phenyl)-urea;
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-m-tolyl--
urea;
1-{4-[1-(2-Methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3--
(3-trifluoromethyl-phenyl)-urea;
1-{4-[1-(2-Methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3-pheny-
l-urea;
1-(2-Fluoro-5-methyl-phenyl)-3-{4-[1-(2-methoxy-ethyl)-1H-pyrazolo-
[3,4-c]pyridin-4-yl]-phenyl}-urea;
1-{2-Fluoro-4-[1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(3-trifluoromethyl-phenyl)-urea;
1-{2-Fluoro-4-[1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-methyl-pyridi-
n-4-yl)-urea;
1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-
-yl)-phenyl]-urea;
1-[4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(5-tert-Butyl-2-phenyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4--
c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Methyl-piperidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[4-(4-m-
ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-piperidin-1-y-
lmethyl-3-trifluoromethyl-phenyl)-urea;
1-[2-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(4-Dimethylamino-piperidin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-pyrrolidin-1--
yl-5-trifluoromethyl-phenyl)-urea;
1-(2-Dimethylamino-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3-
,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(3-Dimethylamino-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1--
methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-5-trifluoromethyl-phenyl}-3-[-
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-{2-[(3-Dimethylamino-propyl)-methyl-amino]-5-trifluoromethyl-phenyl}-3--
[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(3-Dimethylamino-piperidin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Methanesulfonyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-
-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3--
[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-morpholin-4-y-
lmethyl-3-trifluoromethyl-phenyl)-urea;
1-(5-Isopropyl-2-phenyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c-
]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Methyl-3-oxo-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-
-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Methyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(-
1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(4-Cyano-3-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyr-
idin-4-yl)-phenyl]-urea;
1-(3-Methyl-isoxazol-5-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-
-phenyl]-urea;
1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4--
c]pyridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(6-meth-
yl-pyridin-2-yl)-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-trif-
luoromethyl-pyridin-2-yl)-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-trifluorometh-
yl-oxazol-2-yl)-urea;
1-[2-(3-Fluoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[2-(3-f-
luoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(5-isop-
ropyl-2-phenyl-2H-pyrazol-3-yl)-urea;
1-(5-tert-Butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-1H-pyra-
zolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-p-
yrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-
-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(5-tert-Butyl-2-pyridin-4-yl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazol-
o[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(5-fluoro-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-
-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(5-fluoro-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[2-fluoro-4--
(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-me-
thyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(5-Cyclopropyl-2-phenyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-
-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Methyl-piperazine-1-carbonyl)-3-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(5-Fluoro-pyridin-3-yl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl--
1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[2-(5-f-
luoro-pyridin-3-yl)-5-isopropyl-2H-pyrazol-3-yl]-urea;
1-[5-Isopropyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-
-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[5-isop-
ropyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-urea;
1-[5-Isopropyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(5-Isopropyl-2-m-tolyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4--
c]pyridin-4-yl)-phenyl]-urea;
1-[2-(3-Chloro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(4-Fluoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(3-Chloro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-meth-
yl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[5-isop-
ropyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[5-isop-
ropyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(5-isop-
ropyl-2-m-tolyl-2H-pyrazol-3-yl)-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[2-(4-f-
luoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-urea;
1-(5-Cyclopropyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-{4-[1-(2-Methanesulfonyl-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-
-3-(3-trifluoromethyl-phenyl)-urea;
1-(2,3-Dichloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-ph-
enyl]-urea;
1-(2-Chloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl-
]-urea;
1-(3-Chloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-
-phenyl]-urea;
1-(4-Chloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl-
]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-triflu-
oromethyl-phenyl)-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-m-tolyl-urea;
1-(4-Dimethylaminomethyl-3-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyra-
zolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Methyl-piperidin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(1-me-
thyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
(S)-1-[4-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethyl-phenyl-
]-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Cyclopropylmethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-
-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Hydroxy-piperidin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-{4-[(3-Dimethylamino-propyl)-methyl-amino]-3-trifluoromethyl-phenyl}-3--
[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
[1-(4-{3-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-ureido}-2-t-
rifluoromethyl-phenyl)-piperidin-4-yl]-carbamic acid tert-butyl
ester;
1-[4-((R)-3-Dimethylamino-pyrrolidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-
-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-((S)-3-Dimethylamino-pyrrolidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-
-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
4-(4-{3-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-ureido}-2-tr-
ifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl
ester;
1-{4-[Methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenyl}-3-
-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(1-Methyl-piperidin-4-ylamino)-3-trifluoromethyl-phenyl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(1-Methyl-piperidin-4-yloxy)-3-trifluoromethyl-phenyl]-3-[4-(1-methy-
l-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(4-Dimethylamino-piperidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(3-Bromo-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-
-urea;
1-(2,4-Dichloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4--
yl)-phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trifluorometh-
oxy-phenyl)-urea;
1-(3-Chloro-4-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea;
1-(3-Isopropyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phe-
nyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-
-3-[5-isopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-2H-pyrazol-3-yl]-urea;
1-[5-Isopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(-
1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-(5-Isopropyl-2-pyridin-3-yl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo-
[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(5-isop-
ropyl-2-pyridin-3-yl-2H-pyrazol-3-yl)-urea;
1-[5-Isopropyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(3,5-difluoro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-
-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(3,5-difluoro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-meth-
yl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(3-Fluoro-4-methoxy-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(3-Fluoro-4-methoxy-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(3,5-dichloro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-
-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(3,5-dichloro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(5-fluoro-2-methyl-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(5-fluoro-2-methyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[5-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[2-(3-Fluoro-4-methyl-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-meth-
yl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea;
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[4-(piperidin-4--
ylamino)-3-trifluoromethyl-phenyl]-urea;
1-[4-(4-Amino-piperidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-methyl-1H-
-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea; and
1-[3-Chloro-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-[4-(1-methyl-1H-p-
yrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea.
12. A method of preparing a compound of general formula (I)
according to any claim 1, said method comprising the step of
allowing an intermediate compound of general formula 11:
##STR00226## in which A, B, D, E, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and q are as defined in claim 1, to
undergo a deamination, via a diazotization with an appropriate
diazotizing agent, such as NaNO.sub.2, and a subsequent
de-diazotization, with an acid, such as sulphuric or hydrochloric
acid, thus providing a compound of general formula (I):
##STR00227## in which A, B, D, E, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and q are as defined in claim 1.
13. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula 1: ##STR00228## in
which D, R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined
in claim 1, to undergo a reaction with an isocyanate of formula
(Ia'): ##STR00229## in which B, E, R.sup.4, and R.sup.5 are as
defined in claim 1, thus providing a compound of general formula
(Ia): ##STR00230## in which B, D, E, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and q are as defined in claim 1.
14. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula 1: ##STR00231## in
which D, R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined
in claim 1, to react with a compound of general formula 2:
##STR00232## in which B, E, R.sup.4, and R.sup.5 are defined as in
claim 1; in the presence of a phosgene equivalent, such as
triphosgene, thus providing a compound of general formula (Ia):
##STR00233## in which B, D, E, R.sup.a, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5 and q are as defined in claim 1.
15. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula 12: ##STR00234## in
which D, R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined
in claim 1, to react with a compound of general formula 2:
##STR00235## in which B, E, R.sup.4, and R.sup.5 are defined as in
claim 1; preferably in the presence of a base, such as
N-methylpyrrolidine, thus providing a compound of general formula
(Ia): ##STR00236## in which B, D, E, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and q are as defined in claim 1.
16. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula 1: ##STR00237## in
which D, R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined
in claim 1, to react with a compound of general formula 13:
##STR00238## in which B, E, R.sup.4, and R.sup.5 are defined as in
claim 1; preferably in the presence of a base, such as
N-methylpyrrolidine, thus providing a compound of general formula
(Ia): ##STR00239## in which B, D, E, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and q are as defined in claim 1.
17. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula 14: ##STR00240## in
which D, R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined
in claim 1, to react with a compound of general formula 2:
##STR00241## in which B, E, R.sup.4, and R.sup.5 are defined as in
claim 1; preferably in the presence of a base, such as pyridine,
thus providing a compound of general formula (Ia): ##STR00242## in
which B, D, E, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and q are as defined in claim 1.
18. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula 1: ##STR00243## in
which D, R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined
in claim 1, to react with a compound of general formula 15:
##STR00244## in which B, E, R.sup.4, and R.sup.5 are defined as in
claim 1; preferably in the presence of a base, such as pyridine,
thus providing a compound of general formula (Ia): ##STR00245## in
which B, D, E, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and q are as defined in claim 1.
19. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula 3: ##STR00246## in
which R.sup.1 and R.sup.2 are as defined in claim 1, and X is Cl,
Br, or I, to react in a coupling reaction with a compound of
general formula 5: ##STR00247## in which A, B, D, E, R.sup.a,
R.sup.3, R.sup.4, R.sup.5 and q are as defined in claim 1, and R is
H or alkyl; thus providing a compound of general formula (I):
##STR00248## in which A, B, D, E, R.sup.a, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and q are as defined in claim 1.
20. A method of preparing a compound of general formula (I)
according to claim 1, said method comprising the step of allowing
an intermediate compound of general formula Ib: ##STR00249## in
which A, B, D, E, R.sup.a, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and q
are as defined in claim 1; to undergo a reaction with a reagent of
formula 12, R.sup.1--X 12, in which R.sup.1 is as defined in claim
1 and X represents a leaving group such as Cl, Br or I; thus
providing a compound of general formula (I'): ##STR00250## in which
A, B, D, E, R.sup.a, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5
and q are as defined in claim 1, with the proviso that R.sup.1 is
not H.
21. A pharmaceutical composition which comprises a compound
according to claim 1, and a pharmaceutically acceptable diluent or
carrier.
22-31. (canceled)
32. A method of treating a disease of dysregulated vascular growth
or diseases which are accompanied with dysregulated vascular growth
by administering an effective amount of a compound of general
formula (I) according to claim 1.
33. The method according to claim 32, wherein said disease are
tumors and/or metastases thereof.
34. The method according to claim 32, wherein said diseases are
selected from chronic myelogeneous leukaemia, acute myelogenous
leukaemia, acute lymphatic leukaemia, acute lymphocytic leukaemia,
chronic lymphocytic leukaemia, chronic lymphatic leukaemia as well
as other myeloid precursor hyperplasias such as polycythemia vera
and myelofibrosis.
35. The method according to claim 32, wherein said disease are
retinopathy, other angiogenesis dependent diseases of the eye, in
particular cornea transplant rejection or age-related macular
degeneration.
36. The method according to claim 32, wherein said disease are
rheumatoid arthritis, and other inflammatory diseases associated
with angiogenesis, in particular psoriasis, delayed type
hypersensitivity, contact dermatitis, asthma, multiple sclerosis,
restenosis, pulmonary hypertension, stroke, and inflammatory
diseases of the bowel, such as, Crohn's disease.
37. The method according to claim 32, wherein said disease are
coronary and peripheral artery disease and for the suppression of
atherosclerotic plaque formation.
38. The method according to claim 32, wherein said disease are
diseases associated with stromal proliferation or characterized by
pathological stromal reactions diseases associated with deposition
of fibrin or extracellular matrix, such as, fibrosis, cirrhosis,
carpal tunnel syndrome.
39. The method according to claim 32, wherein said disease are
gynaecological diseases where inhibition of angiogenic,
inflammatory and stromal processes with pathological character can
be inhibited, such as, endometriosis, pre-eclampsia, postmenopausal
bleeding and ovarian hyperstimulation.
40. The method according to claim 32, wherein said disease are
ascites, oedema such as brain tumor associated oedema, high
altitude trauma, hypoxia induced cerebral oedema, pulmonary oedema
and macular oedema or oedema following burns and trauma, chronic
lung disease, adult respiratory distress syndrome, bone resorption
and benign proliferating diseases such as myoma, benign prostate
hyperplasia.
41. The method according to claim 32 for supporting wound healing,
particularly for the reduction of scar formation, and for the
reduction of scar formation during regeneration of damaged
nerves.
42. A compound of general formula 1: ##STR00251## in which D,
R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined in claim
1.
43. A compound of general formula 12: ##STR00252## in which D,
R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined in claim
1.
44. A compound of general formula 14: ##STR00253## in which D,
R.sup.a, R.sup.1, R.sup.2, R.sup.3, and q are as defined in claim
1.
45-49. (canceled)
Description
[0001] The present invention relates to 3-H-pyrazolopyridine
compounds of general formula (I) and salts, N-oxides, solvates and
prodrugs thereof, to pharmaceutical compositions comprising said
3-H-pyrazolopyridine compounds, to methods of preparing said
3-H-pyrazolopyridines, to intermediate compounds useful in said
methods, to uses of said intermediate compounds in the preparation
of said 3-H-pyrazolopyridines, as well as to uses of said
3-H-pyrazolopyridines.
SCIENTIFIC BACKGROUND
[0002] Dysregulated vascular growth plays a critical role in a
variety of inflammatory diseases, in particular psoriasis, delayed
type hypersensitivity, contact dermatitis, asthma, multiple
sclerosis, restenosis, rheumatoid arthritis and inflammatory bowl
disease. Aberrant vascular growth is also involved in neovascular
ocular diseases such as age-related macular degeneration and
diabetic retinopathy. Additionally, sustained vascular growth is
accepted as one hallmark of cancer development (Hanahan, D.;
Weinberg, R. A. Cell 2000, 100, 57). While tumors initially grow
either as an avascular mass or by co-opting existing host vessels,
growth beyond a few mm.sup.3 in size is depending on the induction
of vessel neogrowth in order to sufficiently provide the tumor with
oxygen and nutrients. Induction of angiogenesis is a prerequisite
that the tumor surpasses a certain size (the so called angiogenic
switch). An intricate signalling interaction network between cancer
cells and the tumor microenvironment triggers the induction of
vessel growth from existing vasculature. The dependence of tumors
on neovascularization has led to a new treatment paradigm in cancer
therapy (Ferrara et al. Nature 2005, 438, 967; Carmeliet Nature
2005, 438, 932). Blocking tumor neovascularization by small
molecule or antibody-mediated inhibition of relevant signal
transduction pathways holds a great promise for extending currently
available therapy options.
[0003] The development of the cardiovascular system involves two
basic stages. In the initial vasculogenesis stage, which only
occurs during embryonal development, angioblasts differentiate into
endothelial cells which subsequently form a primitive vessel
network. The subsequent stage, termed angiogenesis, involves the
remodeling of the initial vasculature and sprouting of new vessels
(Risau, W. Nature 1997, 386, 671; Jain, R. K. Nat. Med. 2003, 9,
685). Physiologically, angiogenesis occurs in wound healing, muscle
growth, the female cycle and in the above mentioned disease
states.
[0004] It has been found that receptor tyrosine kinases of the
vascular endothelial growth factor (VEGF) family and the Tie
(tyrosine kinase with immunoglobulin and epidermal growth factor
homology domain) receptor tyrosine kinases are essential for both
developmental and disease-associated angiogenesis (Ferrara et al
Nat. Med. 2003, 9, 669; Dumont et al. Genes Dev. 1994, 8, 1897;
Sato et al. Nature 1995, 376, 70).
[0005] In adults the Tie2 receptor tyrosine kinase is selectively
expressed on endothelial cells (EC) of the adult vasculature
(Schlaeger et al. Proc. Nat. Acad. Sci. USA 1997, 94, 3058).
Immunohistochemical analysis demonstrated the expression of Tie2 in
adult rat tissues undergoing angiogenesis. During ovarian
folliculogenesis, Tie2 is expressed in neovessels of the developing
corpus luteum. Four endogeneous ligands--angiopoietins 1 to 4--have
been identified for the type 1 transmembrane Tie2 (also named Tek)
receptor, while no ligands have been identified so far for the Tie1
receptor. Binding of the extracellular Tie2 domain to the
C-terminal fibrinogen-like domains of the various angiopoietins
leads to significantly different cellular effects. In addition,
heterodimerizations between Tie1 and Tie2 receptors have been
postulated to influence ligand binding.
[0006] Binding of Ang1 to Tie2 expressed on EC induces receptor
cross-phosphorylation and kinase activation thus triggering various
intracellular signalling pathways. The intracellular C-terminal
tail of the Tie2 protein plays a crucial role in Tie2 signalling
(Shewchuk et al. Structure 2000, 8, 1105). Upon ligand binding, a
conformational change is induced which removes the C-tail out of
its inhibitory conformation thus allowing kinase activation by
cross-phoshorylation of various Tyr residues in the C-tail, which
subsequently function as docking sites for phosphotyrosine-binding
(PTB) site possessing down-stream mediators. Cellular effects
initiated by Ang1 activation of Tie2 include inhibition of EC
apoptosis, stimulation of EC migration and blood vessel
reorganization, suppression of inflammatory gene expression and
suppression of vascular permeability (Brindle et al. Circ. Res.
2006, 98, 1014). In contrast to VEGF-VEGFR signalling in EC, Ang1
activation of Tie2 does not stimulate EC proliferation in the
majority of published assay settings.
[0007] The anti-apoptotic effect of Tie2 signalling was shown to be
mediated mainly by the PI3K-Akt signalling axis which is activated
by binding of the regulatory p85 subunit of PI3K to Y1102 in the
Tie2 C-tail (DeBusk et al. Exp. Cell. Res. 2004, 298, 167;
Papapetropoulos et al. J. Biol. Chem. 2000, 275, 9102; Kim et al.
Circ. Res. 2000, 86, 24). In contrast, the chemotactic response
downstream of the activated Tie2 receptor requires crosstalk
between PI3K and the adaptor protein Dok-R. Membrane localization
of Dok-R via binding of its pleckstrin homology (PH) domain to PI3K
and simultaneous binding to Y1108 in the Tie2 C-tail via its PTB
domain leads to Dok-R phoshorylation and downstream signalling via
Nck and Pak-1 (Jones et al. Mol. Cell. Biol. 2003, 23, 2658; Master
et al. EMBO J. 2001, 20, 5919). PI3K-mediated recruitment of the
adaptor protein ShcA to Y1102 of the Tie2 C-tail is also believed
to induce cellular sprouting and motility effects involving
activation of endothelial nitric oxide synthase (eNOS), focal
adhesion kinase (FAK) and the GTPases RhoA and Rac1. Other
downstream mediators of Tie2 signalling include the adaptor protein
Grb2, which mediates Erk1/2 stimulation, and the SHP-2
phosphatase.
[0008] In conclusion, basal activation of the Tie2 pathway by Ang1
is believed to maintain quiescence and integrity of the endothelium
of the adult vasculature by providing a cell survival signal for
ECs and by maintaining the integrity of the EC lining of blood
vessels (Peters et al. Recent Prog. Horm. Res. 2004, 59, 51).
[0009] In contrast to Ang1, Ang2 is not able to activate Tie2 on EC
unless Ang2 is present in high concentration or for prolonged
periods. However, Ang2 functions as a Tie2 agonist in
non-endothelial cells transfected with Tie2. The structural basis
for this context-dependence of the Ang2-Tie2 interaction is to date
not understood.
[0010] In endothelial cells, however, Ang2 functions as Tie2
antagonist and thus blocks the agonistic activity of Ang1
(Maisonpierre et al. Science 1997, 277, 55). Ang2 binding to Tie2
prevents Ang1-mediated Tie2 activation which leads to vessel
destabilization and results in vessel regression in the absence of
pro-angiogenic stimuli such as VEGF. While Ang1 is widely expressed
by periendothelial cells in quiescent vasculature such as pericytes
or smooth muscle cells, Ang2 expression occurs in areas of ongoing
angiogenesis. Ang2 can be stored in Weibel-Palade bodies in the
cytoplasm of EC allowing for a quick vascular response upon
stimulation.
[0011] Ang1 and Ang2 are expressed in the corpus luteum, with Ang2
localizing to the leading edge of proliferating vessels and Ang1
localizing diffusively behind the leading edge. Ang2 expression is
inter alia initiated by hypoxia (Pichiule et al. J. Biol. Chem.
2004, 279, 12171). Ang2 is upregulated in the tumor vasculature and
represents one of the earliest tumor markers. In the hypoxic tumor
tissue, Ang2 expression induces vessel permeability and--in the
presence of e.g. pro-angiogenic VEGF--triggers angiogenesis. After
VEGF mediated EC proliferation and vessel sprouting maturation of
the newly formed vessels again necessitates Tie2 activation by
Ang1. Therefore, a subtle balancing of Tie2 activity plays a
pivotal role in the early as well as late stages of
neovascularization. These observations render the Tie2 RTK an
attractive target for anti-angiogenesis therapy in diseases caused
by or associated with dysregulated vascular growth. However, it
remains to be shown if targeting the Tie2 pathway alone will be
sufficient to achieve efficacious blockade of neovascularization.
In certain diseases or disease subtypes it might be necessary or
more efficacious to block several angiogenesis-relevant signalling
pathways simultaneously. In certain oncological diseases it might
be beneficial to block angiogenesis-relevant signalling pathways
and, in addition, certain kinases, the activity of which plays a
critical role for cancer cell proliferation and/or invasion of
surrounding tissues by cancer cells. For example, activity of Ret
kinase has been shown to play a critical role in certain forms of
e.g. thyroid cancer. Simultaneous inhibition of
angiogenesis-relevant signalling pathways, for example of Tie2
signalling, and Ret kinase activity may therefore be more
efficacious for the treatment of these forms of e.g. thyroid cancer
than inhibition of angiogenesis alone. The tyrosine kinase TrkB is
often overexpressed in human cancers and it has been implied that
TrkB signalling promotes tumor formation and metastasis (see for
example Desmet, C. J.; Peeper, D. S. Cell. Mol. Life. Sci. 2006,
63, 755). Simultaneous inhibition of angiogenesis-relevant
signalling pathways, for example of Tie2 signalling, and TrkB
kinase activity may therefore be more efficacious for treating
tumors, which are characterized by increased TrkB activity, than
inhibition of angiogenesis alone.
[0012] Various theories have been discussed to explain the
differential effects of Ang1 and Ang2 on Tie2 downstream signalling
events. Binding of Ang1 and Ang2 in a structurally different manner
to the Tie2 ectodomain could induce ligand-specific conformational
changes of the intracellular kinase domain explaining different
cellular effects. Mutational studies however point toward similar
binding sites of Ang1 and Ang2. In contrast, various publications
have focussed on different oligomerization states of Ang1 vs. Ang2
as basis for different receptor multimerization states upon ligand
binding. Only Ang1 present in its tetramer or higher-order
structure initiates Tie2 activation in EC while Ang2 was reported
to exist as a homodimer in its native state (Kim et al. J. Biol.
Chem. 2005, 280, 20126; Davis et al. Nat. Struc. Biol. 2003, 10,
38; Barton et al. Structure 2005, 13, 825). Finally, specific
interactions of Ang1 or Ang2 with additional cell-specific
co-receptors could be responsible for the different cellular
effects of Ang1 vs. Ang2 binding to Tie2. Interaction of Ang1 with
integrin .alpha.5.beta.1 has been reported to be essential for
certain cellular effects (Carlson et al. J. Biol. Chem. 2001, 276,
26516; Dallabrida et al. Circ. Res. 2005, 96, e8). Integrin
.alpha.5.beta.1 associates constitutively with Tie2 and increases
the receptor's binding affinity for Ang1 resulting in initiation of
downstream signalling at lower Ang1 effector concentrations in
situations where integrin .alpha.5.beta.1 is present. The recently
solved crystal structure of the Tie2-Ang2 complex suggests however
that neither the oligomerization state nor a different binding mode
causes the opposing cellular effects (Barton et al. Nat. Struc.
Mol. Biol. 2006, advance online publication).
[0013] Ang1-Tie2 signalling plays also a role in the development of
the lymphatic system and in lymphatic maintenance and sprouting
(Tammela et al. Blood 2005, 105, 4642). An intimate cross-talk
between Tie2 and VEGFR-3 signalling in lymphangiogenesis seems to
equal the Tie2-KDR cross-talk in blood vessel angiogenesis.
[0014] A multitude of studies have underscored the functional
significance of Tie2 signalling in the development and maintenance
of the vasculature. Disruption of Tie2 function in Tie2.sup.-/-
transgenic mice leads to early embryonic lethality between days 9.5
and 12.5 as a consequence of vascular abnormalities. Tie2.sup.-/-
embryos fail to develop the normal vessel hierachy suggesting a
failure of vascular branching and differentiation. The heart and
vessels in Tie2.sup.-/- embryos show a decreased lining of EC and a
loosened interaction between EC and underlying pericyte/smooth
muscle cell matrix. Mice lacking functional Ang1 expression and
mice overexpressing Ang2 display a phenotype reminiscent of the
phenotype of Tie2.sup.-/- mice (Suri et al. Cell 1996, 87, 1171).
Ang2.sup.-/- mice have profound defects in the growth and
patterning of lymphatic vasculature and fail to remodel and regress
the hyaloid vasculature of the neonatal lens (Gale et al. Dev. Cell
2002, 3, 411). Ang1 rescued the lymphatic defects, but not the
vascular remodeling defects. Therefore, Ang2 might function as a
Tie2 antagonist in blood vasculature but as a Tie2 agonist in
developing lymph vasculature suggesting redundant roles of Ang1 and
Ang2 in lymphatic development.
[0015] Aberrant activation of the Tie2 pathway is involved in
various pathological settings. Activating Tie2 mutations leading to
increased ligand-dependent and ligand-independent Tie2 kinase
activity cause inherited venous malformations (Vikkula et al. Cell
1996, 87, 1181). Increased Ang1 mRNA and protein levels as well as
increased Tie2 activation have been reported in patients with
pulmonary hypertension (PH). Increased pulmonary arterial pressure
in PH patients results from increased coverage of pulmonary
arterioles with smooth muscle cells (Sullivan et al. Proc. Natl.
Acad. Sci. USA 2003, 100, 12331). In chronic inflammatory diseases,
like in psoriasis, Tie2 and the ligands Ang1 and Ang2 are greatly
upregulated in lesions, whereas a significant decrease in
expression of Tie2 and ligands occur under anti-psoriatic treatment
(Kuroda et al. J. Invest. Dermatol 2001, 116, 713). Direct
association of pathogenesis of disease with Tie2 expression has
been demonstrated recently in transgenic mice overexpressing Tie2
(Voskas et al. Am. J. Pathol. 2005, 166, 843). In these mice
overexpression of Tie2 causes a psoriasis-like phenotype (such as
epidermal thickening, rete ridges and lymphocyte infiltration).
These skin abnormalities are resolved completely upon suppression
of transgene expression, thereby illustrating a complete dependence
on Tie2 signalling for disease maintenance and progression. A
recent study underscored the connection of the Ang1/Ang2-Tie2
signalling axis to the induction of inflammation (Fiedler et al.
Nat. Med. 2006, 12, 235). Inhibition of the Tie2 signalling pathway
is therefore expected to be useful in the therapy of a broad range
of inflammatory diseases.
[0016] Tie2 expression was investigated in human breast cancer
specimens and Tie2 expression was found in the vascular endothelium
both in normal breast tissue as well as in tumor tissue. The
proportion of Tie2-positive microvessels was increased in tumors as
compared to normal breast tissue (Peters et al. Br. J. Canc. 1998,
77, 51). However, significant heterogeneity in endothelial Tie2
expression was observed in clinical specimen from a variety of
human cancers (Fathers et al. Am. J. Path. 2005, 167, 1753). In
contrast, Tie2 and angiopoietins were found to be highly expressed
in the cytoplasm of human colorectal adenocarcinoma cells
indicating at the potential presence of an autocrine/paracrine
growth loop in certain cancers (Nakayama et al. World J.
Gastroenterol. 2005, 11, 964). A similar autocrine/paracrine
Ang1-Ang2-Tie2 loop was postulated for certain human gastric cancer
cell lines (Wang et al. Biochem. Biophys. Res. Comm. 2005, 337,
386). In addition, it was observed clinically that Ang2 is
overexpressed in the bone marrow of AML (acute myelogenous
leukemia) patients and Tie2 is additionally overexpressed in
leukemic blasts (Schliemann et al. 2006, 91, 1203). Taking into
account that Ang1-Tie2 signalling regulates hematopoietic stem cell
quiescence in the bone marrow niche, Tie2 inhibition would
therefore force promyeloid cells into differentiation resulting in
purging the bone marrow from leukemic precursor cells (Arai et al.
Cell 2004, 118, 149).
[0017] The relevance of the Ang1-Tie2 signalling axis was
challenged with various biochemical techniques. Inhibition of Ang1
expression by an antisense RNA approach resulted in decreased
xenograft tumor growth (Shim et al. Int. J. Canc. 2001, 94, 6; Shim
et al. Exp. Cell Research 2002, 279, 299). However, other studies
report that experimental overexpression of Ang1 in tumor models
leads to decreased tumor growth (Hayes et al. Br. J. Canc. 2000,
83, 1154; Hawighorst et al. Am. J. Pathol. 2002, 160, 1381;
Stoeltzing et al. Cancer Res. 2003, 63, 3370). The latter results
can be rationalized by the ligand's ability to stabilize the
endothelial lining of vessels rendering vessels less sensitive for
angiogenic stimuli. Interference with the dynamics of Ang1-Tie2
signalling either by over-stimulation or by stimulus deprivation
seemingly leads to similar phenotypes.
[0018] The pharmacological relevance of inhibiting Tie2 signalling
was tested applying various non-small molecule approaches. A
peptidic inhibitor of Ang1/2 binding to Tie2 was shown to inhibit
Ang1-induced HUVEC migration and angiogenesis induction in an in
vivo model (Tournaire et al. EMBO Rep. 2005, 5, 1). Corneal
angiogenesis induced by tumor cell conditioned medium was inhibited
by a recombinant soluble Tie2 receptor (sTie2) despite the presence
of VEGF (Lin et al. J. Clin. Invest. 1997, 100, 2072; see also
Singh et al. Biochem. Biophys. Res. Comm. 2005, 332, 194). Gene
therapy by adenoviral vector delivered sTie2 was capable of
reducing tumor growth rates of a murine mammary carcinoma and a
murine melanoma and resulted in reduction of metastasis formation
(Lin et al. Proc. Natl. Acad. Sci. USA 1998, 95, 8829). Similar
effects were observed with related sTie2 constructs (Siemeister et
al. Cancer Res. 1999, 59, 3185) and a Tek-Fc construct (Fathers et
al. Am. J. Path. 2005, 167, 1753).
[0019] Adenovirus-delivered anti-Tie2 intrabodies were shown to
inhibit growth of a human Kaposi's sarcoma and a human colon
carcinoma upon peritumoral administration (Popkov et al. Cancer
Res. 2005, 65, 972). Histopathological analysis revealed a marked
decrease in vessel density in treated vs. control tumors.
Phenotypic simultaneous knockout of KDR and Tie2 by an adenovirus
delivered intradiabody resulted in significantly higher growth
inhibition of a human melanoma xenograft model than KDR knockout
alone (Jendreyko et al. Proc. Natl. Acad. Sci. USA 2005, 102,
8293). Similarly, the bispecific Tie2-KDR intradiabody was more
active in an in vitro EC tube formation inhibition assay than the
two monospecific intrabodies alone (Jendreyko et al. J. Biol. Chem.
2003, 278, 47812). Systematic treatment of tumor-bearing mice with
Ang2-blocking antibodies and peptide-Fc fusion proteins led to
tumor stasis and elimination of tumor burden in a subset of animals
(Oliner et al. Cancer Cell 2004, 6, 507). For a recent report on an
immunization approach, see Luo et al. Clin. Cancer Res. 2006, 12,
1813.
[0020] However, from the above studies using biochemical techniques
to interfere with Tie2 signalling it is not clear, whether similar
phenotypes will be observed with small molecule inhibitors of the
Tie2 kinase activity. Small molecule inhibitors of kinases by
definition block only those cellular effects which are mediated by
the receptor's kinase activity and not those which might involve
the kinase only as a co-receptor or scaffolding component in
multi-enzyme complexes. So far, only a single study using a small
molecule Tie2 inhibitor has been published (Scharpfenecker et al.
J. Cell Sci. 2005, 118, 771). It remains to be shown that small
molecule inhibitors of the Tie2 kinase will be as efficacious in
inhibiting angiogenesis as e.g. ligand antibodies, soluble decoy
receptors or receptor intrabodies.
PRIOR ART
[0021] To date, a small number of therapeutic agents with
antiangiogenic activity have been approved for cancer treatment.
Avastin (Bevacizumab), a VEGF neutralizing antibody, blocks KDR and
VEGFR1 signalling and has been approved for first-line treatment of
metastatic colorectal cancer. The small molecule multi-targeted
kinase inhibitor Nexavar.RTM. (Sorafenib) inhibits inter alia
members of the VEGFR family and has been approved for the treatment
of advanced renal cell carcinoma. Sutent (Sunitinib), another
multi-targeted kinase inhibitor with activity vs. VEGFR family
members, has been approved by the FDA for treatment of patients
with gastrointestinal stromal tumors (GIST) or advanced kidney
tumors. Several other small molecule inhibitors of
angiogenesis-relevant targets are in clinical and pre-clinical
development.
[0022] AMG-386, an angiopoietin-targeting recombinant Fc fusion
protein, is in phase I clinical development in patients with
advanced solid tumors. Several multi-targeted small molecule
inhibitors with activity against Tie2 are (or have been) in
preclinical evaluation for cancer therapy, including ABT-869,
GW697465A and A-422885.88 (BSF466895). The first and most recent
compound (Abt-869), however, was reported to be >10 times more
potent against at least 5 other kinase targets than against Tie2.
In addition, Abt-869 has been reported to possess only modest
activity as inhibitor of cellular Tie2 autophosphorylation (Albert
et al. Mol. Cancer. Ther. 2006, 5, 995).
[0023] Pyrazolopyridines have been disclosed as antimicrobiotic
substances (e.g. Attaby et al., Phosphorus, Sulfur and Silicon and
the related Elements 1999, 149, 49-64; Goda et al. Bioorg. Med.
Chem. 2004, 12, 1845). U.S. Pat. No. 5,478,830 further discloses
fused heterocycles for the treatment of atherosclerosis.
Pyrazolopyridines have also been described as PDE4-Inhibitors
(WO2006004188, US20060004003).
[0024] A single 3-amino-1H-pyrazolo[3,4-b]pyridine with modest EGFR
inhibitory activity has been published by Cavasotto et al. (Bioorg.
Med. Chem. Lett. 2006, 16, 1969).
5-aryl-1H-3-aminopyrazolo[3,4-b]pyridines have been reported as
GSK-3 inhibitors (Witherington et al. Bioorg. Med. Chem. Lett.
2003, 13, 1577). WO 2003068773 discloses 3-aminopyrazolopyridine
derivatives as GSK-3 inhibitors.
[0025] WO 2004113304 (covering Abt-869, see above) discloses
3-amino-indazoles as inhibitors of protein tyrosine kinases,
particularly as inhibitors as KDR kinase. WO 2006050109,
WO2006077319 and WO2006077168 disclose 3-aminopyrazolopyridines as
tyrosine kinase inhibitors.
[0026] WO 2002024679 discloses tetrahydropyridine-substituted
pyrazolopyridines as IKK inhibitors. WO 2004076450 further
discloses 5-heteroaryl-pyrazolopyridines as p38 inhibitors.
US20040192653 and US20040176325 inter alia disclose
4-H-pyrazolopyridines as p38 inhibitors. WO2005044181 discloses
pyrazolopyridines as Abl kinase inhibitors.
TECHNICAL PROBLEM TO BE SOLVED
[0027] There is a great need for novel chemotypes for small
molecule inhibitors of the Tie2 kinase, in particular inhibitors
not only of the isolated kinase domain, but more importantly of
cellular Tie-2 autophosphorylation. Fine tuning of additive
anti-angiogenic activities as well as pharmacokinetic parameters
such as e.g. solubility, membrane permeability, tissue distribution
and metabolism will finally allow for choosing compounds of
suitable profiles for various diseases caused by or associated with
dysregulated vascular growth. Additional Inhibition of specific
kinases, the activity of which is not relevant for angiogenesis but
e.g. for tumor cell proliferation or invasion of surrounding
tissues by tumor cells would be of special importance in treating
certain diseases e.g. oncological diseases. However, compounds with
purely antiangiogenic activity would be of special importance for
e.g. the treatment of non-oncological diseases caused by or
associated with dysregulated vascular growth.
[0028] It would be desirable to have compounds at one's disposal
which display selectivity within the class of tyrosine kinases
since inhibition of a broad spectrum of tyrosine kinases and side
effects resulting thereof would limit pharmaceutical applications
of those compounds. It would be especially desirable to have
compounds at one's disposal which display potent inhibition of Tie2
while being significantly less active as inhibitors of specific
other tyrosine kinases, particularly as inhibitors of the insulin
receptor kinase (InsR).
[0029] Inhibition of InsR kinase may result in disadvantageous
effects on the liver. The insulin/IGF-1 receptor inhibitor
NVP-ADW742 for example at concentrations which inhibit both the
insulin and IGF-1 receptors strongly potentiated desoxycholic
acid-induced apoptotic cell death, which as a consequence predicts
strong liver toxic effects in case of impaired bile flow (Dent et
al. Biochem. Pharmacol. 2005, 70, 1685). Even worse, inhibition of
the neuronal insulin receptor causes Alzheimer-like disturbances in
oxidative/energy brain metabolism (Hoyer et al. Ann. N.Y. Acad.
Sci. 1999, 893, 301).
[0030] It is known to the person skilled in the art that small
structural changes to scaffolds previously used as kinase
inhibitors will significantly impact selectivity profiles in an
unpredictable manner. Inhibition of kinases by using
ATP-competitive heteroaromatic compounds is well precedented in the
patent and scientific literature (Parang, K.; Sun, G. Curr. Opin.
Drug Disc. 2004, 7, 617: Design Strategies for protein kinase
inhibitors.). It is known to the person skilled in the art that
ATP-competitive compounds bind to the ATP-binding site in kinases
by forming a hydrogen bonding network to a distinct region of the
enzyme (the so called hinge region). 3-Aminopyrazoles were shown to
form such a hydrogen bonding network to a kinase hinge region
including the amino group of the 3-aminopyrazole moiety
(Witherington et al.: "5-aryl-pyrazolo[3,4-b]pyridines: Potent
inhibitors of glycogen synthase kinase-3" Bioorg. Med. Chem. Lett.
2003, 13, 1577). Prior art as cited above revealed 3-aminoindazoles
and 3-aminopyrazolopyridines as inhibitors of various tyrosine
kinases, e.g. of Tie2 kinase. In general, it would be desirable to
have compounds at hand with a reduced number of H-bond donors--e.g.
inhibitor compounds based on a scaffold lacking a primary amino
group--in order to improve physicochemical or pharmacokinetic
characteristics. However, the person skilled in the art would
expect that removing the amino group in the 3-position of the
pyrazole ring of the above cited prior art compounds should disrupt
hydrogen bonding interactions of these inhibitors with e.g. the
Tie2 kinase hinge region and therefore should lead to compounds
with significantly reduced activity as kinase inhibitors.
DESCRIPTION OF THE INVENTION
[0031] Surprisingly, it was now found that compounds of the present
invention, which feature a pyrazolopyridine scaffold lacking the
3-amino group, not only display potent activity as inhibitors of
Tie2 kinase activity and as inhibitors of cellular Tie2
autophosphorylation. Even more surprisingly, compounds of the
present invention display an advantageous selectivity profile
within in the class of tyrosine kinases, with more selective
inhibition of Tie2 kinase relative to inhibition of other, not
desired tyrosine kinases, particularly the insulin receptor kinase
(InsR). Such a pharmacological profile is highly desirable not only
for treating diseases of dysregulated vascular growth or diseases
which are accompanied with dysregulated vascular growth, in
particular solid tumors and metastases thereof, but also for
treating non-oncological diseases of dysregulated vascular growth
or non-oncological diseases which are accompanied with dysregulated
vascular growth, such as, for example, retinopathy, other
angiogenesis dependent diseases of the eye, in particular cornea
transplant rejection or age-related macular degeneration,
rheumatoid arthritis, and other inflammatory diseases associated
with angiogenesis, in particular psoriasis, delayed type
hypersensitivity, contact dermatitis, asthma, multiple sclerosis,
restenosis, pulmonary hypertension, stroke, and diseases of the
bowel, diseases such as coronary and peripheral artery disease,
wherein treatment of the said non-oncological diseases is
preferably accomplished with less side-effects than in the
treatment of oncological diseases. In addition, inhibition of one
or more further specific tyrosine kinase(s) by compounds of the
present invention, the activity of which is (are) of relevance for
the pathogenesis of certain oncological diseases, allows for the
use of preferred compounds of the present invention for the
treatment of these oncological diseases.
[0032] The solution to the above-mentioned novel technical problem
is achieved by providing compounds derived, in accordance with the
present invention, from a class of 3-H-pyrazolopyridines and salts,
N-oxides, solvates and prodrugs thereof, methods of preparing
3-H-pyrazolopyridines, a pharmaceutical composition containing said
3-H-pyrazolopyridines, use of said 3-H-pyrazolopyridines and a
method for treating diseases with said 3-H-pyrazolopyridines, all
in accordance with the description, as defined in the claims of the
present application.
[0033] The compounds of Formula (I) below, salts, N-oxides,
solvates and prodrugs thereof are collectively referred to as the
"compounds of the present invention". The invention thus relates to
compounds of general formula (I):
##STR00002##
in which: [0034] R.sup.1 represents H or --C(O)R.sup.b, or is
selected from the group comprising, preferably consisting of,
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, wherein said residues are
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; [0035] R.sup.2 represents hydrogen,
halogen, --NR.sup.d1R.sup.d2, --OR.sup.c, --C(O)R.sup.b, or is
selected from the group comprising, preferably consisting of,
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, heteroaryl, wherein said
residues are unsubstituted or one or more times substituted
independently from each other with R.sup.7; [0036] R.sup.3 is
selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, hydroxy,
amino, halogen, and cyano; [0037] R.sup.4, R.sup.5, R.sup.6,
R.sup.7 independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2,
wherein C.sub.1-C.sub.6-alkyl, aryl, heteroaryl,
C.sub.3-C.sub.10-heterocycloalkyl and C.sub.3-C.sub.10-cycloalkyl
are optionally substituted one or more times by R.sup.8; [0038]
R.sup.8 is selected from the group comprising, preferably
consisting of, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2;
[0039] R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and C.sub.1-C.sub.6-alkyl; [0040] R.sup.b
is selected from the group comprising, preferably consisting of,
hydroxyl, OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2,
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with hydroxyl, halogen, or
C.sub.1-C.sub.6-alkoxy; [0041] R.sup.c is selected from the group
comprising, preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
aryl, --OR.sup.f, --NR.sup.d1R.sup.d2, or --OP(O)(OR.sup.f).sub.2;
[0042] R.sup.d1, R.sup.d2 independently from each other are
selected from the group comprising, preferably consisting of
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl are optionally substituted one or more times,
the same way or differently with halogen, hydroxy or the group
aryl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; or [0043] R.sup.d1
and R.sup.d2 together with the nitrogen atom to which they are
attached, form a 3 to 10 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, halogen,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted one or more times, the same way or differently, by a
member of the group comprising, preferably consisting of, NH,
NR.sup.d3, oxygen or sulphur, and can optionally be interrupted one
or more times, the same way or differently, with a --C(O)--,
--S(O)--, and/or --S(O).sub.2-- group, and can optionally contain
one or more double bonds [0044] R.sup.d3 is selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, hydroxyl,
halogen, C.sub.1-C.sub.6-haloalkyl or C.sub.1-C.sub.6-alkoxy;
[0045] R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and
heteroaryl; [0046] R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; [0047]
R.sup.g1, R.sup.g2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl; [0048]
R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they
are attached, form a 3 to 10 membered heterocycloalkyl ring, which
is optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted one or more
times, the same way or differently, by a member of the group
comprising, preferably consisting of, NH, NR.sup.a, oxygen or
sulphur, and can optionally be interrupted one or more times, the
same way or differently, with a --C(O)--, --S(O)--, and/or
--S(O).sub.2-- group, and can optionally contain one or more double
bonds; [0049] A is selected from the group comprising, preferably
consisting of, --C(O)--, --C(S)--, --C(.dbd.NR.sup.a)--,
--C(O)NR.sup.a--, --C(.dbd.NR.sup.a)NR.sup.a--, --S(O).sub.2--,
--S(O)(.dbd.NR.sup.a)--, --S(.dbd.NR.sup.a).sub.2--,
--C(S)NR.sup.a--, --C(O)C(O)--, --C(O)C(O)NR.sup.a--,
--C(O)NR.sup.aC(O)--, --C(S)NR.sup.aC(O)--, and
--C(O)NR.sup.aC(S)--; [0050] B is a bond or selected from the group
comprising, preferably consisting of C.sub.1-C.sub.6-alkylene,
C.sub.3-C.sub.10-cycloalkylene, and
C.sub.3-C.sub.10-heterocycloalkylene; [0051] D, E are,
independently from each other, arylene or heteroarylene [0052] and
[0053] q represents an integer of 0, 1, or 2 [0054] or a salt, an
N-oxide, a solvate or a prodrug thereof, wherein, when one or more
of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3,
R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are) present
in one position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different. For example, when R.sup.a is present twice in the
molecule, then the meaning of the first R.sup.a may be H, for
example, and the meaning of the second R.sup.a may be methyl, for
example.
[0055] In accordance with a preferred embodiment, the present
invention relates to compounds of formula I, supra, wherein [0056]
R.sup.1 represents H or --C(O)R.sup.b, or is selected from the
group comprising, preferably consisting of, C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl, C.sub.2-C.sub.6-alkynyl,
C.sub.3-C.sub.10-cycloalkyl, and C.sub.3-C.sub.10-heterocycloalkyl,
wherein said residues are unsubstituted or substituted one or more
times, independently from each other, with R.sup.6; [0057] R.sup.2
represents hydrogen, halogen, --NR.sup.d1R.sup.d2, --OR.sup.c, or
--C(O)R.sup.b, or is selected from the group comprising, preferably
consisting of, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.2-C.sub.6-alkynyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein
said residues are unsubstituted or one or more times substituted
independently from each other with R.sup.7; [0058] R.sup.3 is
selected from the group comprising, preferably consisting of,
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy,
C.sub.1-C.sub.6-haloalkyl, C.sub.1-C.sub.6-haloalkoxy, hydroxy,
amino, halogen, and cyano; [0059] R.sup.4, R.sup.5, R.sup.6,
R.sup.7 independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2,
wherein C.sub.1-C.sub.6-alkyl, aryl, heteroaryl,
C.sub.3-C.sub.10-heterocycloalkyl and C.sub.3-C.sub.10-cycloalkyl
are optionally substituted one or more times by R.sup.8; [0060]
R.sup.8 is selected from the group comprising, preferably
consisting of, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.1-C.sub.6-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, --NR.sup.d1R.sup.d2, and --OP(O)(OR.sup.c).sub.2;
[0061] R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and C.sub.1-C.sub.6-alkyl; [0062] R.sup.b
is selected from the group comprising, preferably consisting of,
hydroxyl, --OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2,
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with hydroxyl, halogen, or
C.sub.1-C.sub.6-alkoxy; [0063] R.sup.c is selected from the group
comprising, preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
aryl, --OR.sup.f, --NR.sup.d1R.sup.d2, or --OP(O)(OR.sup.f).sub.2;
[0064] R.sup.d1, R.sup.d2 independently from each other are
selected from the group comprising, preferably consisting of
hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl are optionally substituted one or more times,
the same way or differently with halogen, hydroxy or the group
aryl, --NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e, --OP(O)(OR.sup.f).sub.2; or [0065] R.sup.d1
and R.sup.d2 together with the nitrogen atom to which they are
attached, form a 3 to 10 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, halogen,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e, or --OP(O)(OR.sup.f).sub.2; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted one or more times, the same way or differently, by a
member of the group comprising, preferably consisting of, NH,
NR.sup.d3, oxygen or sulphur, and can optionally be interrupted one
or more times, the same way or differently, with a --C(O)--,
--S(O)--, and/or --S(O).sub.2-- group, and can optionally contain
one or more double bonds [0066] R.sup.d3 is selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.6-alkyl, and C.sub.3-C.sub.10-cycloalkyl are
optionally substituted one or more times with
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl, hydroxyl,
halogen, C.sub.1-C.sub.6-haloalkyl or C.sub.1-C.sub.6-alkoxy;
[0067] R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.6-alkoxy, aryl and
heteroaryl; [0068] R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-haloalkyl,
C.sub.3-C.sub.10-cycloalkyl, C.sub.3-C.sub.10-heterocycloalkyl,
aryl, and heteroaryl, wherein C.sub.1-C.sub.6-alkyl,
C.sub.1-C.sub.6-haloalkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.6-alkoxy, aryl, or --NR.sup.g1R.sup.g2; [0069]
R.sup.g1, R.sup.g2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.10-cycloalkyl,
C.sub.3-C.sub.10-heterocycloalkyl, aryl, and heteroaryl; [0070]
R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they
are attached, form a 3 to 10 membered heterocycloalkyl ring, which
is optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.6-alkyl, --C.sub.1-C.sub.6-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted one or more
times, the same way or differently, by a member of the group
comprising, preferably consisting of, NH, NR.sup.a, oxygen or
sulphur, and can optionally be interrupted one or more times, the
same way or differently, with a --C(O)--, --S(O)--, and/or
--S(O).sub.2-- group, and can optionally contain one or more double
bonds [0071] A represents --C(O)-- or --C(O)NR.sup.a--; [0072] B is
a bond or selected from the group comprising, preferably consisting
of C.sub.1-C.sub.3-alkylene and C.sub.3-C.sub.5-cycloalkylene;
[0073] D, E are, independently from each other, arylene or
heteroarylene [0074] and [0075] q represents an integer of 0, or 1;
wherein, when one or more of R.sup.a, R.sup.b, R.sup.c, R.sup.d1,
R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or
R.sup.8 is (are) present in one position in the molecule as well as
in one or more further positions in the molecule, said R.sup.a,
R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f,
R.sup.g1, R.sup.g2, or R.sup.8 has (have), independently from each
other, the same meanings as defined above in said first position in
the molecule and in said second or further positions in the
molecule, it being possible for the two or more occurrences of
R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e,
R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 within a single molecule to
be identical or different. For example, when R.sup.a is present
twice in the molecule, then the meaning of the first R.sup.a may be
H, for example, and the meaning of the second R.sup.a may be
methyl, for example.
[0076] In accordance with a more preferred embodiment, the present
invention relates to compounds of formula I, supra, wherein: [0077]
R.sup.1 represents H, C.sub.1-C.sub.6-alkyl, or
C.sub.2-C.sub.6-alkenyl, wherein C.sub.1-C.sub.6-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; [0078] R.sup.2 represents hydrogen,
halogen, --NR.sup.d1R.sup.d2, --OR.sup.c, --C(O)R.sup.b, or
C.sub.1-C.sub.6-alkyl, wherein C.sub.1-C.sub.6-alkyl is
unsubstituted or one or more times substituted independently from
each other with R.sup.7; [0079] R.sup.3 is selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, and cyano; [0080] R.sup.4, R.sup.5, R.sup.6,
R.sup.7 independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
aryl, heteroaryl, C.sub.3-C.sub.6-heterocycloalkyl and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times by R.sup.8; [0081] R.sup.8 is selected from the group
comprising, preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; [0082]
R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and methyl; [0083] R.sup.b is selected from
the group comprising, preferably consisting of, hydroxyl, OR.sup.c,
--SR.sup.c, --NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; [0084]
R.sup.c is selected from the group comprising, preferably
consisting of, hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times with
hydroxyl, halogen, aryl, --OR.sup.f, or --NR.sup.d1R.sup.d2; [0085]
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times, the
same way or differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or [0086] R.sup.d1 and R.sup.d2 together with
the nitrogen atom to which they are attached, form a 3 to 7
membered heterocycloalkyl ring, which is optionally substituted one
or more times, the same way or differently, with
C.sub.1-C.sub.4-alkyl, halogen, --NR.sup.g1R.sup.g2, --OR.sup.f,
--C(O)R.sup.e, or --S(O).sub.2R.sup.e; whereby the carbon backbone
of this heterocycloalkyl ring can optionally be interrupted one or
more times, the same way or differently, by a member of the group
comprising, preferably consisting of, NH, NR.sup.d3, or oxygen, and
can optionally be interrupted one or more times, the same way or
differently, with a --C(O)-- group; [0087] R.sup.d3 is selected
from the group comprising, preferably consisting of hydrogen and
C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is optionally
substituted one or more times with C.sub.3-C.sub.6-cycloalkyl,
hydroxyl, halogen, C.sub.1-C.sub.4-haloalkyl or
C.sub.1-C.sub.4-alkoxy; [0088] R.sup.e is selected from the group
comprising, preferably consisting of, --NR.sup.g1R.sup.g2,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.1-C.sub.3-alkoxy, aryl and heteroaryl; [0089] R.sup.f is
selected from the group comprising, preferably consisting of,
hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times with
hydroxyl, halogen, C.sub.1-C.sub.3-alkoxy, aryl, or
--NR.sup.g1R.sup.g2; [0090] R.sup.g1, R.sup.g2 independently from
each other are selected from the group comprising, preferably
consisting of hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl; [0091] R.sup.g1 and R.sup.g2 together with the
nitrogen atom to which they are attached, form a 3 to 6 membered
heterocycloalkyl ring, which is optionally substituted one or more
times, the same way or differently, with C.sub.1-C.sub.4-alkyl,
--C.sub.1-C.sub.4-alkoxy, halogen or hydroxy; whereby the carbon
backbone of this heterocycloalkyl ring can optionally be
interrupted one or more times, the same way or differently, by a
member of the group comprising, preferably consisting of, NH,
NR.sup.a, or oxygen; [0092] A represents --C(O)NR.sup.a--; [0093] B
is a bond; [0094] D, E are, independently from each other, arylene
or heteroarylene [0095] and [0096] q is 0; wherein, when one or
more of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3,
R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are) present
in one position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different. For example, when R.sup.a is present twice in the
molecule, then the meaning of the first R.sup.a may be H, for
example, and the meaning of the second R.sup.a may be methyl, for
example.
[0097] In accordance with a more particularly preferred embodiment,
the present invention relates to compounds of formula I, supra,
wherein [0098] R.sup.1 represents H, C.sub.1-C.sub.6-alkyl, or
C.sub.2-C.sub.6-alkenyl, wherein C.sub.1-C.sub.6-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; [0099] R.sup.2 represents hydrogen,
halogen, --NR.sup.d1R.sup.d2, --OR.sup.c, --C(O)R.sup.b, or
C.sub.1-C.sub.6-alkyl, wherein C.sub.1-C.sub.6-alkyl is
unsubstituted or one or more times substituted independently from
each other with R.sup.7; [0100] R.sup.3 is selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, and cyano; [0101] R.sup.4, R.sup.5, R.sup.6,
R.sup.7 independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
aryl, heteroaryl, C.sub.3-C.sub.6-heterocycloalkyl and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times by R.sup.8; [0102] R.sup.8 is selected from the group
comprising, preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; [0103]
R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and methyl; [0104] R.sup.b is selected from
the group comprising, preferably consisting of, hydroxyl,
--OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl,
and C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; [0105]
R.sup.c is selected from the group comprising, preferably
consisting of, hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times with
hydroxyl, halogen, aryl, --OR.sup.f, or --NR.sup.d1R.sup.d2; [0106]
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times, the
same way or differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or [0107] R.sup.d1 and R.sup.d2 together with
the nitrogen atom to which they are attached, form a 3 to 7
membered heterocycloalkyl ring, which is optionally substituted one
or more times, the same way or differently, with
C.sub.1-C.sub.4-alkyl, halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f;
whereby the carbon backbone of this heterocycloalkyl ring can
optionally be interrupted once by a member of the group comprising,
preferably consisting of, NH, NR.sup.d3, or oxygen; [0108] R.sup.d3
represents hydrogen or C.sub.1-C.sub.4-alkyl, wherein
C.sub.1-C.sub.4-alkyl is optionally substituted once by a
C.sub.3-C.sub.6-cycloalkyl, hydroxyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy or halogen; [0109] R.sup.e is selected from
the group comprising, preferably consisting of,
--NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; [0110] R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; [0111]
R.sup.g1, R.sup.g2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; [0112]
R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they
are attached, form a 3 to 6 membered heterocycloalkyl ring, which
is optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted once by a
member of the group comprising, preferably consisting of, NH,
NR.sup.a, or oxygen; [0113] A represents --C(O)NR.sup.a--; [0114] B
is a bond; [0115] D is para-phenylene [0116] E is phenylene or
heteroarylene [0117] and [0118] q is 0; wherein, when one or more
of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3,
R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are) present
in one position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different. For example, when R.sup.a is present twice in the
molecule, then the meaning of the first R.sup.a may be H, for
example, and the meaning of the second R.sup.a may be methyl, for
example.
[0119] In accordance with a more particularly preferred embodiment
still, the present invention relates to compounds of formula I,
supra, wherein: [0120] R.sup.1 represents H, C.sub.1-C.sub.6-alkyl,
or C.sub.2-C.sub.6-alkenyl, wherein C.sub.1-C.sub.6-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; [0121] R.sup.2 represents hydrogen,
halogen, --NR.sup.d1R.sup.d2, --OR.sup.c, --C(O)R.sup.b, or
C.sub.1-C.sub.6-alkyl, wherein C.sub.1-C.sub.6-alkyl is
unsubstituted or one or more times substituted independently from
each other with R.sup.7; [0122] R.sup.3 is selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-alkoxy,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, and cyano; [0123] R.sup.4, R.sup.5, R.sup.6,
R.sup.7 independently from each other, are selected from the group
comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
aryl, heteroaryl, C.sub.3-C.sub.6-heterocycloalkyl and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times by R.sup.8; [0124] R.sup.8 is selected from the group
comprising, preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; [0125]
R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and methyl; [0126] R.sup.b is selected from
the group comprising, preferably consisting of, hydroxyl,
--OR.sup.c, --SR.sup.c, --NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl,
and C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; [0127]
R.sup.c is selected from the group comprising, preferably
consisting of, hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, aryl, and heteroaryl, wherein
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times with
hydroxyl, halogen, aryl, --OR.sup.f, or --NR.sup.d1R.sup.d2; [0128]
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl, or for a
group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times, the
same way or differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or [0129] R.sup.d1 and R.sup.d2 together with
the nitrogen atom to which they are attached, form a 3 to 7
membered heterocycloalkyl ring, which is optionally substituted one
or more times, the same way or differently, with
C.sub.1-C.sub.4-alkyl, halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f;
whereby the carbon backbone of this heterocycloalkyl ring can
optionally be interrupted once by a member of the group comprising,
preferably consisting of, NH, NR.sup.d3, or oxygen; [0130] R.sup.d3
represents hydrogen or C.sub.1-C.sub.4-alkyl, wherein
C.sub.1-C.sub.4-alkyl is optionally substituted once by a
C.sub.3-C.sub.6-cycloalkyl, hydroxyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy or halogen; [0131] R.sup.e is selected from
the group comprising, preferably consisting of,
--NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; [0132] R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; [0133]
R.sup.g1, R.sup.g2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; [0134]
R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they
are attached, form a 3 to 6 membered heterocycloalkyl ring, which
is optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, --C.sub.1-C.sub.4-alkoxy,
halogen or hydroxy; whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted once by a
member of the group comprising, preferably consisting of, NH,
NR.sup.a, or oxygen; [0135] A represents --C(O)NR.sup.a--; [0136] B
is a bond; [0137] D is para-phenylene [0138] E is heteroarylene
[0139] and [0140] q is 0; wherein, when one or more of R.sup.a,
R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f,
R.sup.g1, R.sup.g2, or R.sup.8 is (are) present in one position in
the molecule as well as in one or more further positions in the
molecule, said R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2,
R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 has
(have), independently from each other, the same meanings as defined
above in said first position in the molecule and in said second or
further positions in the molecule, it being possible for the two or
more occurrences of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2,
R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 within a
single molecule to be identical or different. For example, when
R.sup.a is present twice in the molecule, then the meaning of the
first R.sup.a may be H, for example, and the meaning of the second
R.sup.a may be methyl, for example.
[0141] In accordance with an even more particularly preferred
embodiment, the present invention relates to compounds of formula
I, supra, wherein: [0142] R.sup.1 represents H or
C.sub.1-C.sub.4-alkyl wherein C.sub.1-C.sub.4-alkyl is
unsubstituted or substituted one or more times with R.sup.6; [0143]
R.sup.2 represents hydrogen; [0144] R.sup.3 is selected from the
group comprising, preferably consisting of, hydrogen, methyl,
methoxy, fluorine and hydroxy; [0145] R.sup.4 is selected from the
group comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.4-alkyl, C.sub.1-C.sub.6-cycloalkyl, wherein
C.sub.1-C.sub.4-alkyl is optionally substituted by R.sup.8; [0146]
R.sup.5 is selected from the group comprising, preferably
consisting of, hydrogen, C.sub.1-C.sub.4-alkyl,
C.sub.5-C.sub.6-heterocycloalkyl, C.sub.5-C.sub.6-cycloalkyl,
phenyl and pyridyl, wherein C.sub.1-C.sub.4-alkyl,
C.sub.5-C.sub.6-heterocycloalkyl, C.sub.5-C.sub.6-cycloalkyl,
phenyl and pyridyl are optionally substituted one or more times,
independently from each other, with R.sup.8; [0147] R.sup.6,
represents hydroxy; [0148] R.sup.8 is selected from the group
comprising, preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2; [0149] R.sup.a represents
hydrogen or methyl; [0150] R.sup.b is selected from the group
comprising, preferably consisting of, hydroxy, --OR.sup.c,
--NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, [0151] R.sup.c represents
C.sub.1-C.sub.3-alkyl or C.sub.6-C.sub.7-heterocycloalkyl; [0152]
R.sup.d1, R.sup.d2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen, and
C.sub.1-C.sub.3-alkyl, or [0153] R.sup.d1 and R.sup.d2 together
with the nitrogen atom to which they are attached, form a 3 to 7
membered heterocycloalkyl ring, which is optionally substituted one
or more times, the same way or differently, with
C.sub.1-C.sub.4-alkyl, halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f;
whereby the carbon backbone of this heterocycloalkyl ring can
optionally be interrupted once by a member of the group comprising,
preferably consisting of, NH, NR.sup.d3, or oxygen; [0154] R.sup.d3
represents hydrogen or C.sub.1-C.sub.4-alkyl, wherein
C.sub.1-C.sub.4-alkyl is optionally substituted once by a
C.sub.3-C.sub.6-cycloalkyl, hydroxy, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy or halogen; [0155] R.sup.g1, R.sup.g2
independently from each other are selected from the group
comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl and C.sub.3-C.sub.6-cycloalkyl; [0156] A
represents --C(O)NR.sup.a--; [0157] B is a bond; [0158] D is a
para-phenylene [0159] E is a pyrazole; [0160] and [0161] q is 0;
wherein, when one or more of R.sup.a, R.sup.c, or R.sup.d3 is (are)
present in one position in the molecule as well as in one or more
further positions in the molecule, said R.sup.a, R.sup.c, or
R.sup.d3 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.c, or
R.sup.d3 within a single molecule to be identical or different. For
example, when R.sup.a is present twice in the molecule, then the
meaning of the first R.sup.a may be H, for example, and the meaning
of the second R.sup.a may be methyl, for example.
[0162] In accordance with a variant, the present invention relates
to compounds of formula I, supra, wherein [0163] R.sup.1 represents
H, or C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; [0164] R.sup.2 represents hydrogen,
halogen, --NR.sup.d1R.sup.d2, --OR.sup.c, --C(O)R.sup.b, or
C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or one or more times substituted independently from
each other with R.sup.7; [0165] R.sup.3 is selected from the group
comprising, preferably consisting of, hydrogen, methyl, methoxy,
hydroxy, halogen, and cyano; [0166] R.sup.4, R.sup.5 independently
from each other, are selected from the group comprising, preferably
consisting of, hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
amino, halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-heterocycloalkyl and C.sub.3-C.sub.6-cycloalkyl are
optionally substituted one or more times by R.sup.8; [0167] R.sup.6
independently from each other, are selected from the group
comprising, preferably consisting of, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, hydroxy, halogen, cyano,
--C(O)R.sup.b, --S(O).sub.2R.sup.b, --OR.sup.c, and
--NR.sup.d1R.sup.d2; [0168] R.sup.7 independently from each other,
are selected from the group comprising, preferably consisting of,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl,
hydroxy, halogen, cyano, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2; [0169] R.sup.8 is selected
from the group comprising, preferably consisting of,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.7-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, aryl, heteroaryl, hydroxy, amino,
halogen, cyano, nitro, --C(O)R.sup.b, --S(O).sub.2R.sup.b,
--OR.sup.c, and --NR.sup.d1R.sup.d2; [0170] R.sup.a is selected
from the group comprising, preferably consisting of, hydrogen and
methyl; [0171] R.sup.b is selected from the group comprising,
preferably consisting of, hydroxyl, --OR.sup.c,
--NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; [0172]
R.sup.c is selected from the group comprising, preferably
consisting of, hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.7-heterocycloalkyl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl are optionally substituted one or
more times with hydroxyl, halogen, aryl, --OR.sup.f, or
--NR.sup.d1R.sup.d2; [0173] R.sup.d1, R.sup.d2 independently from
each other are selected from the group comprising, preferably
consisting of hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, and C.sub.3-C.sub.6-heterocycloalkyl,
or for a group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl are optionally substituted one or more times, the
same way or differently with halogen, hydroxy or the group aryl,
--NR.sup.g1R.sup.g2, --OR.sup.f, --C(O)R.sup.e,
--S(O).sub.2R.sup.e; or [0174] R.sup.d1 and R.sup.d2 together with
the nitrogen atom to which they are attached, form a 3 to 7
membered heterocycloalkyl ring, which is optionally substituted one
or more times, the same way or differently, with
C.sub.1-C.sub.4-alkyl, halogen, --NR.sup.g1R.sup.g2, or --OR.sup.f;
whereby the carbon backbone of this heterocycloalkyl ring can
optionally be interrupted once by a member of the group comprising,
preferably consisting of, NH, NR.sup.d3, or oxygen; [0175] R.sup.d3
represents hydrogen or C.sub.1-C.sub.4-alkyl, wherein
C.sub.1-C.sub.4-alkyl is optionally substituted once by a
C.sub.3-cycloalkyl, hydroxyl, C.sub.1-C.sub.4-haloalkyl,
C.sub.1-C.sub.4-alkoxy or halogen; [0176] R.sup.e is selected from
the group comprising, preferably consisting of,
--NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; [0177] R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; [0178]
R.sup.g1, R.sup.g2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; [0179]
R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they
are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby
the carbon backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; [0180] A represents
--C(O)NR.sup.a--; [0181] B is a bond; [0182] D is para-phenylene
[0183] E is phenylene [0184] and [0185] q is 0; wherein, when one
or more of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3,
R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are) present
in one position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different. For example, when R.sup.a is present twice in the
molecule, then the meaning of the first R.sup.a may be H, for
example, and the meaning of the second R.sup.a may be methyl, for
example.
[0186] In accordance with a preferred embodiment of the
above-mentioned variant, the present invention relates to compounds
of formula I, supra, wherein: [0187] R.sup.1 represents H, or
C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; [0188] R.sup.2 represents hydrogen;
[0189] R.sup.3 is selected from the group comprising, preferably
consisting of, hydrogen, methyl, methoxy, hydroxy, and halogen;
[0190] R.sup.4, R.sup.5 independently from each other, are selected
from the group comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, hydroxy, amino, halogen, cyano, nitro,
--C(O)R.sup.b, --S(O).sub.2R.sup.b, --OR.sup.c, and
--NR.sup.d1R.sup.d2, wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-heterocycloalkyl and C.sub.3-C.sub.6-cycloalkyl are
optionally substituted one or more times by R.sup.8; [0191] R.sup.6
independently from each other, are selected from the group
comprising, preferably consisting of, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, hydroxy, halogen, cyano,
--C(O)R.sup.b, --S(O).sub.2R.sup.b, --OR.sup.c, and
--NR.sup.d1R.sup.d2; [0192] R.sup.8 is selected from the group
comprising, preferably consisting of, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, aryl,
heteroaryl, hydroxy, amino, halogen, cyano, nitro, --C(O)R.sup.b,
--S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2; [0193]
R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and methyl; [0194] R.sup.b is selected from
the group comprising, preferably consisting of, hydroxyl,
--OR.sup.c, --NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl, wherein C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl are optionally substituted one or more
times with hydroxyl, halogen, or C.sub.1-C.sub.3-alkoxy; [0195]
R.sup.c is selected from the group comprising, preferably
consisting of, hydrogen, --C(O)R.sup.e, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.7-heterocycloalkyl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.6-heterocycloalkyl are optionally substituted one or
more times with hydroxyl, halogen, aryl, --OR.sup.f, or
--NR.sup.d1R.sup.d2; [0196] R.sup.d1, R.sup.d2 independently from
each other are selected from the group comprising, preferably
consisting of hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, and C.sub.3-C.sub.6-heterocycloalkyl,
or for a group --C(O)R.sup.e, --S(O).sub.2R.sup.e, or
--C(O)NR.sup.g1R.sup.g2 wherein C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, and C.sub.3-C.sub.6-heterocycloalkyl
are optionally substituted one or more times, the same way or
differently with halogen, hydroxy or the group --NR.sup.g1R.sup.g2,
--OR.sup.f, --C(O)R.sup.e, --S(O).sub.2R.sup.e; or [0197] R.sup.d1
and R.sup.d2 together with the nitrogen atom to which they are
attached, form a 3 to 7 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, halogen,
--NR.sup.g1R.sup.g2, or --OR.sup.f; whereby the carbon backbone of
this heterocycloalkyl ring can optionally be interrupted once by a
member of the group comprising, preferably consisting of, NH,
NR.sup.d3, or oxygen; [0198] R.sup.d3 represents hydrogen or
C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is optionally
substituted once by a C.sub.3-cycloalkyl, hydroxyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or halogen;
[0199] R.sup.e is selected from the group comprising, preferably
consisting of, --NR.sup.g1R.sup.g2, C.sub.1-C.sub.3-alkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.1-C.sub.3-alkoxy, aryl and
heteroaryl; [0200] R.sup.f is selected from the group comprising,
preferably consisting of, hydrogen, --C(O)R.sup.e,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.6-heterocycloalkyl, aryl,
and heteroaryl, wherein C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl are
optionally substituted one or more times with hydroxyl, halogen,
C.sub.1-C.sub.3-alkoxy, aryl, or --NR.sup.g1R.sup.g2; [0201]
R.sup.g1, R.sup.g2 independently from each other are selected from
the group comprising, preferably consisting of hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, aryl, and heteroaryl; [0202]
R.sup.g1 and R.sup.g2 together with the nitrogen atom to which they
are attached, form a 3 to 6 membered heterocycloalkyl ring, whereby
the carbon backbone of this heterocycloalkyl ring can optionally be
interrupted once by a member of the group comprising, preferably
consisting of, NH, NR.sup.d3, or oxygen; [0203] A represents
C(O)NR.sup.a--; [0204] B is a bond; [0205] D is para-phenylene
[0206] E is phenylene [0207] and [0208] q is 0; wherein, when one
or more of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3,
R.sup.e, R.sup.f, R.sup.g1, R.sup.g2, or R.sup.8 is (are) present
in one position in the molecule as well as in one or more further
positions in the molecule, said R.sup.a, R.sup.b, R.sup.c,
R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1, R.sup.g2,
or R.sup.8 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, R.sup.e, R.sup.f, R.sup.g1,
R.sup.g2, or R.sup.8 within a single molecule to be identical or
different. For example, when R.sup.a is present twice in the
molecule, then the meaning of the first R.sup.a may be H, for
example, and the meaning of the second R.sup.a may be methyl, for
example.
[0209] In accordance with a more preferred embodiment of the
above-mentioned variant, the present invention relates to compounds
of formula I, supra, wherein: [0210] R.sup.1 represents H, or
C.sub.1-C.sub.3-alkyl, wherein C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times, independently from
each other, with R.sup.6; [0211] R.sup.2 represents hydrogen;
[0212] R.sup.3 is selected from the group comprising, preferably
consisting of, hydrogen, methyl, methoxy, hydroxy, and halogen;
[0213] R.sup.4, R.sup.5 independently from each other, are selected
from the group comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl,
C.sub.3-C.sub.6-heterocycloalkyl, C.sub.1-C.sub.3-haloalkyl,
C.sub.1-C.sub.3-haloalkoxy, hydroxy, amino, halogen, cyano, nitro,
--C(O)R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2, wherein
C.sub.1-C.sub.3-alkyl and C.sub.3-C.sub.6-heterocycloalkyl are
optionally substituted one or more times by R.sup.8; [0214]
R.sup.6, represents hydroxy; [0215] R.sup.8 is selected from the
group comprising, preferably consisting of,
C.sub.3-C.sub.6-cycloalkyl, C.sub.3-C.sub.7-heterocycloalkyl,
C.sub.1-C.sub.3-haloalkyl, C.sub.1-C.sub.3-haloalkoxy, hydroxy,
halogen, --S(O).sub.2R.sup.b, --OR.sup.c, and --NR.sup.d1R.sup.d2;
[0216] R.sup.a is selected from the group comprising, preferably
consisting of, hydrogen and methyl; [0217] R.sup.b is selected from
the group comprising, preferably consisting of, hydroxyl,
--OR.sup.c, --NR.sup.d1R.sup.d2, C.sub.1-C.sub.3-alkyl, and
C.sub.3-C.sub.6-cycloalkyl; [0218] R.sup.c is selected from the
group comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl
C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.7-heterocycloalkyl;
[0219] R.sup.d1, R.sup.d2 independently from each other are
selected from the group comprising, preferably consisting of
hydrogen, C.sub.1-C.sub.3-alkyl, C.sub.3-C.sub.6-cycloalkyl, and
C.sub.3-C.sub.6-heterocycloalkyl, or for a group --C(O)R.sup.e, or
--S(O).sub.2R.sup.e wherein C.sub.1-C.sub.3-alkyl, is optionally
substituted one or more times, the same way or differently with
halogen, hydroxy or C.sub.1-C.sub.3-alkoxy; [0220] R.sup.d1 and
R.sup.d2 together with the nitrogen atom to which they are
attached, form a 3 to 7 membered heterocycloalkyl ring, which is
optionally substituted one or more times, the same way or
differently, with C.sub.1-C.sub.4-alkyl, halogen,
--NR.sup.g1R.sup.g2, or --OR.sup.f; whereby the carbon backbone of
this heterocycloalkyl ring can optionally be interrupted once by a
member of the group comprising, preferably consisting of, NH,
NR.sup.d3, or oxygen; [0221] R.sup.d3 represents hydrogen or
C.sub.1-C.sub.4-alkyl, wherein C.sub.1-C.sub.4-alkyl is optionally
substituted once by a C.sub.3-cycloalkyl, hydroxyl,
C.sub.1-C.sub.4-haloalkyl, C.sub.1-C.sub.4-alkoxy or halogen;
[0222] R.sup.e represents C.sub.1-C.sub.3-alkyl or
C.sub.3-C.sub.6-cycloalkyl; [0223] A represents C(O)NR.sup.a--;
[0224] B is a bond; [0225] D is para-phenylene [0226] E is
phenylene [0227] and [0228] q is 0; wherein, when one or more of
R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, or R.sup.8
is (are) present in one position in the molecule as well as in one
or more further positions in the molecule, said R.sup.a, R.sup.b,
R.sup.c, R.sup.d1, R.sup.d2, R.sup.d3, or R.sup.8 has (have),
independently from each other, the same meanings as defined above
in said first position in the molecule and in said second or
further positions in the molecule, it being possible for the two or
more occurrences of R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2,
R.sup.d3, or R.sup.8 within a single molecule to be identical or
different. For example, when R.sup.a is present twice in the
molecule, then the meaning of the first R.sup.a may be H, for
example, and the meaning of the second R.sup.a may be methyl, for
example.
[0229] In accordance with an even more preferred embodiment of the
above-mentioned variant, the present invention relates to compounds
of formula I, supra, wherein [0230] R.sup.1 represents H or
C.sub.1-C.sub.3-alkyl wherein said C.sub.1-C.sub.3-alkyl is
unsubstituted or substituted one or more times with R.sup.6; [0231]
R.sup.2 represents hydrogen; [0232] R.sup.3 is selected from the
group comprising, preferably consisting of, hydrogen, methyl,
fluorine, hydroxy and methoxy; [0233] R.sup.4 is selected from the
group comprising, preferably consisting of, hydrogen,
C.sub.1-C.sub.3-alkyl, C.sub.1-C.sub.3-haloalkyl, halogen, and
--OR.sup.c, wherein C.sub.1-C.sub.3-alkyl is optionally substituted
by R.sup.8; [0234] R.sup.5 is selected from the group comprising,
preferably consisting of, hydrogen, C.sub.1-C.sub.3-alkyl,
C.sub.1-C.sub.3-haloalkyl, halogen, and --OR.sup.c; [0235] R.sup.6,
represents hydroxy; [0236] R.sup.8 is selected from the group
comprising, preferably consisting of, C.sub.6-heterocycloalkyl,
--OR.sup.c, and --NR.sup.d1R.sup.d2; [0237] R.sup.a represents
hydrogen or methyl; [0238] R.sup.c represents C.sub.1-C.sub.3-alkyl
or C.sub.6-heterocycloalkyl; [0239] R.sup.d1, R.sup.d2
independently from each other are selected from the group
comprising, preferably consisting of hydrogen, and
C.sub.1-C.sub.6-alkyl, or [0240] R.sup.d1 and R.sup.d2 together
with the nitrogen atom to which they are attached, form a 6
membered heterocycloalkyl ring, whereby the carbon backbone of this
heterocycloalkyl ring can optionally be interrupted by a member of
the group comprising, preferably consisting of, NH, NR.sup.d3, or
oxygen; [0241] R.sup.d3 represents hydrogen or methyl; [0242] A
represents --C(O)NR.sup.a--; [0243] B is a bond; [0244] D is a
para-phenylene [0245] E is phenylene; [0246] and [0247] q is 0;
wherein, when one or more of R.sup.a, R.sup.c, or R.sup.d3 is (are)
present in one position in the molecule as well as in one or more
further positions in the molecule, said R.sup.a, R.sup.c, or
R.sup.d3 has (have), independently from each other, the same
meanings as defined above in said first position in the molecule
and in said second or further positions in the molecule, it being
possible for the two or more occurrences of R.sup.a, R.sup.c, or
R.sup.d3 within a single molecule to be identical or different. For
example, when R.sup.a is present twice in the molecule, then the
meaning of the first R.sup.a may be H, for example, and the meaning
of the second R.sup.a may be methyl, for example.
DEFINITIONS
[0248] Within the context of the present application, the terms as
mentioned in this description and in the claims have preferably the
following meanings:
[0249] The term "alkyl" is to be understood as preferably meaning
branched and unbranched alkyl, meaning e.g. methyl, ethyl,
n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, sec-butyl,
pentyl, iso-pentyl, hexyl, heptyl, octyl, nonyl and decyl and
isomers thereof.
[0250] The term "haloalkyl" is to be understood as preferably
meaning branched and unbranched alkyl, as defined supra, in which
one or more of the hydrogen substituents is replaced in the same
way or differently with halogen. Particularly preferably, said
haloalkyl is, e.g. chloromethyl, fluoropropyl, fluoromethyl,
difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,
pentafluoroethyl, bromobutyl, trifluoromethyl, iodoethyl, and
isomers thereof.
[0251] The term "alkoxy" is to be understood as preferably meaning
branched and unbranched alkoxy, meaning e.g. methoxy, ethoxy,
propyloxy, iso-propyloxy, butyloxy, iso-butyloxy, tert-butyloxy,
sec-butyloxy, pentyloxy, iso-pentyloxy, hexyloxy, heptyloxy,
octyloxy, nonyloxy, decyloxy, undecyloxy and dodecyloxy and isomers
thereof.
[0252] The term "haloalkoxy" is to be understood as preferably
meaning branched and unbranched alkoxy, as defined supra, in which
one or more of the hydrogen substituents is replaced in the same
way or differently with halogen, e.g. chloromethoxy, fluoromethoxy,
pentafluoroethoxy, fluoropropyloxy, difluoromethyloxy,
trichloromethoxy, 2,2,2-trifluoroethoxy, bromobutyloxy,
trifluoromethoxy, iodoethoxy, and isomers thereof.
[0253] The term "cycloalkyl" is to be understood as preferably
meaning a C.sub.3-C.sub.10 cycloalkyl group, more particularly a
saturated cycloalkyl group of the indicated ring size, meaning e.g.
a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, or cyclodecyl group; and also as meaning an
unsaturated cycloalkyl group containing one or more double bonds in
the C-backbone, e.g. a C.sub.3-C.sub.10 cycloalkenyl group, such
as, for example, a cyclopropenyl, cyclobutenyl, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or
cyclodecenyl group, wherein the linkage of said cycloalkyl group to
the rest of the molecule can be provided to the double or single
bond; and also as meaning such a saturated or unsaturated
cycloalkyl group being optionally substituted one or more times,
independently from each other, with a C.sub.1-C.sub.6 alkyl group
and/or a halogen and/or an OR.sup.f group and/or a
NR.sup.g1R.sup.g2 group; such as, for example, a
2-methyl-cyclopropyl group, a 2,2-dimethylcyclopropyl group, a
2,2-dimethylcyclobutyl group, a 3-hydroxycyclopentyl group, a
3-hydroxycyclohexylgroup, a 3-dimethylaminocyclobutyl group, a
3-dimethylaminocyclopentyl group or a 4-dimethylaminocyclohexyl
group.
[0254] The term "heterocycloalkyl" is to be understood as
preferably meaning a C.sub.3-C.sub.10 cycloalkyl group, as defined
supra, featuring the indicated number of ring atoms, wherein one or
more ring atom(s) is (are) (a) heteroatom(s) such as NH, NR.sup.d3,
O, S, or (a) group(s) such as a C(O), S(O), S(O).sub.2, or,
otherwise stated, in a C.sub.n-cycloalkyl group, (wherein n is an
integer of 3, 4, 5, 6, 7, 8, 9, or 10), one or more carbon atom(s)
is (are) replaced by said heteroatom(s) or said group(s) to give
such a C.sub.n cycloheteroalkyl group; and also as meaning an
unsaturated heterocycloalkyl group containing one or more double
bonds in the C-backbone, wherein the linkage of said
heterocyclolalkyl group to the rest of the molecule can be provided
to the double or single bond; and also as meaning such a saturated
or unsaturated heterocycloalkyl group being optionally substituted
one or more times, independently from each other, with a
C.sub.1-C.sub.6 alkyl group and/or a halogen and/or an OR.sup.f
group and/or a NR.sup.g1R.sup.g2 group. Thus, said C.sub.n
cycloheteroalkyl group refers, for example, to a three-membered
heterocycloalkyl, expressed as C.sub.3-heterocycloalkyl, such as
oxiranyl (C.sub.3). Other examples of heterocycloalkyls are
oxetanyl (C.sub.4), aziridinyl (C.sub.3), azetidinyl (C.sub.4),
tetrahydrofuranyl (C.sub.5), pyrrolidinyl (C.sub.5), morpholinyl
(C.sub.6), dithianyl (C.sub.6), thiomorpholinyl (C.sub.6),
piperidinyl (C.sub.6), tetrahydropyranyl (C.sub.6), piperazinyl
(C.sub.6), trithianyl (C.sub.6), homomorpholinyl (C.sub.7),
homopiperazinyl (C.sub.7) and chinuclidinyl (C.sub.8); said
cycloheteroalkyl group refers also to, for example,
4-methylpiperazinyl, 3-methyl-4-methylpiperazine,
3-fluoro-4-methylpiperazine, 4-dimethylaminopiperidinyl,
4-methylaminopiperidinyl, 4-aminopiperidinyl,
3-dimethylaminopiperidinyl, 3-methylaminopiperidinyl,
3-aminopiperidinyl, 4-hydroxypiperidinyl, 3-hydroxypiperidinyl,
2-hydroxypiperidinyl, 4-methylpiperidinyl, 3-methylpiperidinyl,
3-dimethylaminopyrrolidinyl, 3-methylaminopyrrolidinyl,
3-aminopyrrolidinyl or methylmorpholinyl.
[0255] The term "halogen" or "Hal" is to be understood as
preferably meaning fluorine, chlorine, bromine, or iodine.
[0256] The term "alkenyl" is to be understood as preferably meaning
branched and unbranched alkenyl, e.g. a vinyl, propen-1-yl,
propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en-1-yl,
but-2-en-2-yl, but-1-en-3-yl, 2-methyl-prop-2-en-1-yl, or
2-methyl-prop-1-en-1-yl group, and isomers thereof.
[0257] The term "alkynyl" is to be understood as preferably meaning
branched and unbranched alkynyl, e.g. an ethynyl, prop-1-yn-1-yl,
but-1-yn-1-yl, but-2-yn-1-yl, or but-3-yn-1-yl group, and isomers
thereof.
[0258] As used herein, the term "aryl" is defined in each case as
having 3-12 carbon atoms, preferably 6-12 carbon atoms, such as,
for example, cyclopropenyl, phenyl, tropyl, indenyl, naphthyl,
azulenyl, biphenyl, fluorenyl, anthracenyl etc, phenyl being
preferred.
[0259] As used herein, the term "heteroaryl" is understood as
meaning an aromatic ring system which comprises 3-16 ring atoms,
preferably 5 or 6 or 9 or 10 atoms, and which contains at least one
heteroatom which may be identical or different, said heteroatom
being such as nitrogen, NH, NR.sup.d3, oxygen, or sulphur, and can
be monocyclic, bicyclic, or tricyclic, and in addition in each case
can be benzocondensed. Preferably, heteroaryl is selected from
thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, thia-4H-pyrazolyl etc., and benzo derivatives
thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl,
benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl,
etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,
etc., and benzo derivatives thereof, such as, for example,
quinolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl,
etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
xanthenyl, or oxepinyl, etc.
[0260] The term "alkylene", as used herein in the context of the
compounds of general formula (I) is to be understood as meaning an
optionally substituted alkyl chain or "tether", having 1, 2, 3, 4,
5, or 6 carbon atoms, i.e. an optionally substituted
--CH.sub.2--("methylene" or "single membered tether" or e.g.
--C(Me).sub.2-), --CH.sub.2--CH.sub.2-- ("ethylene", "dimethylene",
or "two-membered tether"), --CH.sub.2--CH.sub.2--CH.sub.2--
("propylene", "trimethylene", or "three-membered tether"),
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- ("butylene",
"tetramethylene", or "four-membered tether"),
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2-- ("pentylene",
"pentamethylene" or "five-membered ether"), or
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--
("hexylene", "hexamethylene", or six-membered tether") group.
Preferably, said alkylene tether is 1, 2, 3, 4, or 5 carbon atoms,
more preferably 1 or 2 carbon atoms.
[0261] The term "cycloalkylene", as used herein in the context of
the compounds of general formula (I) is to be understood as meaning
an optionally substituted cycloalkyl ring, having 3, 4, 5, 6, 7, 8,
9 or 10, preferably 3, 4, 5, or 6, carbon atoms, i.e. an optionally
substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl ring, preferably
a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
[0262] The term "heterocycloalkylene", as used herein in the
context of the compounds of general formula (I) is to be understood
as meaning a cycloalkylene ring, as defined supra, but which
contains at least one heteroatom which may be identical or
different, said heteroatom being such as NH, NR.sup.d3, oxygen or
sulphur.
[0263] The term "arylene", as used herein in the context of the
compounds of general formula (I) is to be understood as meaning an
optionally substituted monocyclic or polycyclic arylene aromatic
system e.g. arylene, naphthylene and biarylene, preferably an
optionally substituted phenyl ring or "tether", having 6 or 10
carbon atoms. More preferably, said arylene tether is a ring having
6 carbon atoms, i.e. a "phenylene" ring. If the term "arylene" or
e.g. "phenylene" is used it is to be understood that the linking
residues can be arranged to each other in ortho-, para- and
meta-position, eg. an optionally substituted moiety of
structure
##STR00003##
in which linking positions on the rings are shown as non-attached
bonds.
[0264] The term "heteroarylene", as used herein in the context of
the compounds of general formula (I) is to be understood as meaning
an optionally substituted monocyclic or polycyclic heteroarylene
aromatic system, e.g. heteroarylene, benzoheteroarylene, preferably
an optionally substituted 5-membered heterocycle, such as, for
example, furan, pyrrole, pyrazole, thiazole, oxazole, isoxazole, or
thiophene or "tether", or a 6-membered heterocycle, such as, for
example, pyridine, pyrimidine, pyrazine, pyridazine. More
preferably, said heteroarylene tether is a ring having 6 carbon
atoms, e.g. an optionally substituted structure as shown supra for
the arylene moieties, but which contains at least one heteroatom
which may be identical or different, said heteroatom being such as
nitrogen, NH, NR.sup.d3, oxygen, or sulphur. If the term
"heteroarylene" is used it is to be understood that the linking
residues can be arranged to each other in ortho-, para- and
meta-position.
[0265] As used herein, the term "C.sub.1-C.sub.6", as used
throughout this text, e.g. in the context of the definition of
"C.sub.1-C.sub.6-alkyl", or "C.sub.1-C.sub.6-alkoxy", is to be
understood as meaning an alkyl group having a finite number of
carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It
is to be understood further that said term "C.sub.1-C.sub.6" is to
be interpreted as any sub-range comprised therein, e.g.
C.sub.1-C.sub.6, C.sub.2-C.sub.5, C.sub.3-C.sub.4, C.sub.1-C.sub.2,
C.sub.1-C.sub.3, C.sub.1-C.sub.4, C.sub.1-C.sub.5 C.sub.1-C.sub.6;
preferably C.sub.1-C.sub.2, C.sub.1-C.sub.3, C.sub.1-C.sub.4,
C.sub.1-C.sub.5, C.sub.1-C.sub.6; more preferably
C.sub.1-C.sub.3.
[0266] Similarly, as used herein, the term "C.sub.2-C.sub.6", as
used throughout this text, e.g. in the context of the definitions
of "C.sub.2-C.sub.6-alkenyl" and "C.sub.2-C.sub.6-alkynyl", is to
be understood as meaning an alkenyl group or an alkynyl group
having a finite number of carbon atoms of 2 to 6, i.e. 2, 3, 4, 5,
or 6 carbon atoms. It is to be understood further that said term
"C.sub.2-C.sub.6" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.2-C.sub.6, C.sub.3-C.sub.5, C.sub.3-C.sub.4,
C.sub.2-C.sub.3, C.sub.2-C.sub.4, C.sub.2-C.sub.5; preferably
C.sub.2-C.sub.3.
[0267] As used herein, the term "C.sub.3-C.sub.10", as used
throughout this text, e.g. in the context of the definitions of
"C.sub.3-C.sub.10-cycloalkyl" or
"C.sub.3-C.sub.10-heterocycloalkyl", is to be understood as meaning
a cycloalkyl group having a finite number of carbon atoms of 3 to
10, i.e. 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 3, 4, 5
or 6 carbon atoms. It is to be understood further that said term
"C.sub.3-C.sub.10" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.3-C.sub.10, C.sub.4-C.sub.9, C.sub.5-C.sub.8,
C.sub.6-C.sub.7; preferably C.sub.3-C.sub.6.
[0268] As used herein, the term "C.sub.3-C.sub.6", as used
throughout this text, e.g. in the context of the definitions of
"C.sub.3-C.sub.6-cycloalkyl" or "C.sub.3-C.sub.6-heterocycloalkyl",
is to be understood as meaning a cycloalkyl group having a finite
number of carbon atoms of 3 to 6, i.e. 3, 4, 5, or 6 carbon atoms.
It is to be understood further that said term "C.sub.3-C.sub.6" is
to be interpreted as any sub-range comprised therein, e.g.
C.sub.3-C.sub.4, C.sub.4-C.sub.6, C.sub.5-C.sub.6.
[0269] As used herein, the term "C.sub.6-C.sub.11", as used
throughout this text, e.g. in the context of the definitions of
"C.sub.6-C.sub.11-aryl", is to be understood as meaning an aryl
group having a finite number of carbon atoms of 5 to 11, i.e. 5, 6,
7, 8, 9, 10 or 11 carbon atoms, preferably 5, 6, or 10 carbon
atoms. It is to be understood further that said term
"C.sub.6-C.sub.11" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.5-C.sub.10, C.sub.6-C.sub.9, C.sub.7-C.sub.8;
preferably C.sub.5-C.sub.6.
[0270] As used herein, the term "C.sub.5-C.sub.10", as used
throughout this text, e.g. in the context of the definitions of
"C.sub.5-C.sub.10-heteroaryl", is to be understood as meaning a
heteroaryl group having a finite number of carbon atoms of 5 to 10,
in addition to the one or more heteroatoms present in the ring i.e.
5, 6, 7, 8, 9, or 10 carbon atoms, preferably 5, 6, or 10 carbon
atoms. It is to be understood further that said term
"C.sub.5-C.sub.10" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.6-C.sub.9, C.sub.7-C.sub.8, C.sub.7-C.sub.8;
preferably C.sub.5-C.sub.6.
[0271] As used herein, the term "C.sub.1-C.sub.3", as used
throughout this text, e.g. in the context of the definitions of
"C.sub.1-C.sub.3-alkylene", is to be understood as meaning an
alkylene group as defined supra having a finite number of carbon
atoms of 1 to 3, i.e. 1, 2, or 3. It is to be understood further
that said term "C.sub.1-C.sub.3" is to be interpreted as any
sub-range comprised therein, e.g. C.sub.1-C.sub.2, or
C.sub.2-C.sub.3.
[0272] As used herein, the term "one or more times", e.g. in the
definition of the substituents of the compounds of the general
formulae of the present invention, is understood as meaning "one,
two, three, four or five times, particularly one, two, three or
four times, more particularly one, two or three times, even more
particularly one or two times".
[0273] The term "isomers" is to be understood as meaning chemical
compounds with the same number and types of atoms as another
chemical species. There are two main classes of isomers,
constitutional isomers and stereoisomers.
[0274] The term "constitutional isomers" is to be understood as
meaning chemical compounds with the same number and types of atoms,
but they are connected in differing sequences. There are functional
isomers, structural isomers, tautomers or valence isomers.
[0275] In "stereoisomers", the atoms are connected sequentially in
the same way, such that condensed formulae for two isomeric
molecules are identical. The isomers differ, however, in the way
the atoms are arranged in space. There are two major sub-classes of
stereoisomers; conformational isomers, which interconvert through
rotations around single bonds, and configurational isomers, which
are not readily interconvertable.
[0276] Configurational isomers are, in turn, comprised of
enantiomers and diastereomers. Enantiomers are stereoisomers which
are related to each other as mirror images. Enantiomers can contain
any number of stereogenic centers, as long as each center is the
exact mirror image of the corresponding center in the other
molecule. If one or more of these centers differs in configuration,
the two molecules are no longer mirror images. Stereoisomers which
are not enantiomers are called diastereomers.
[0277] In order to limit different types of isomers from each other
reference is made to IUPAC Rules Section E (Pure Appl Chem 45,
11-30, 1976).
FURTHER EMBODIMENTS
[0278] The compounds of the present invention according to Formula
(I) can exist in free form or in a salt form. A suitable
pharmaceutically acceptable salt of the 3-H-pyrazolopyridines of
the present invention may be, for example, an acid-addition salt of
a 3-H-pyrazolopyridine of the invention which is sufficiently
basic, for example, an acid-addition salt with, for example, an
inorganic or organic acid, for example hydrochloric, hydrobromic,
sulphuric, phosphoric, trifluoroacetic, para-toluenesulphonic,
methylsulphonic, citric, tartaric, succinic or maleic acid. In
addition, another suitable pharmaceutically acceptable salt of a
3-H-pyrazolopyridine of the invention which is sufficiently acidic
is an alkali metal salt, for example a sodium or potassium salt, an
alkaline earth metal salt, for example a calcium or magnesium salt,
an ammonium salt or a salt with an organic base which affords a
physiologically acceptable cation, for example a salt with
N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine,
1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinot,
tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,
1-amino-2,3,4-butantriol.
[0279] The compounds of the present invention according to Formula
(I) can exist as N-oxides which are defined in that at least one
nitrogen of the compounds of the general Formula (I) may be
oxidized.
[0280] The compounds of the present invention according to Formula
(I) can exist as solvates, in particular as hydrates, wherein
compounds of the present invention according to Formula (I) may
contain polar solvents, in particular water, as structural element
of the crystal lattice of the compounds. The amount of polar
solvents, in particular water, may exist in a stoichiometric or
unstoichiometric ratio. In case of stoichiometric solvates, e.g.
hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-
etc. solvates or hydrates are possible.
[0281] The compounds of the present invention according to Formula
(I) can exist as prodrugs, e.g. as in vivo hydrolysable esters. As
used herein, the term "in vivo hydrolysable ester" is understood as
meaning an in vivo hydrolysable ester of a compound of formula (I)
containing a carboxy or hydroxyl group, for example, a
pharmaceutically acceptable ester which is hydrolysed in the human
or animal body to produce the parent acid or alcohol. Suitable
pharmaceutically acceptable esters for carboxy groups include for
example alkyl, cycloalkyl and optionally substituted phenylalkyl,
in particular benzyl esters, C.sub.1-C.sub.6 alkoxymethyl esters,
e.g. methoxymethyl, C.sub.1-C.sub.6 alkanoyloxymethyl esters, e.g.
pivaloyloxymethyl, phthalidyl esters, C.sub.3-C.sub.10
cycloalkoxy-carbonyloxy-C.sub.1-C.sub.6 alkyl esters, e.g.
1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters,
e.g. 5-methyl-1,3-dioxolen-2-onylmethyl; and
C.sub.1-C.sub.6-alkoxycarbonyloxyethyl esters, e.g.
1-methoxycarbonyloxyethyl, and may be formed at any carboxy group
in the compounds of this invention. An in vivo hydrolysable ester
of a compound of formula (I) containing a hydroxyl group includes
inorganic esters such as phosphate esters and .alpha.-acyloxyalkyl
ethers and related compounds which as a result of the in vivo
hydrolysis of the ester breakdown to give the parent hydroxyl
group. Examples of .alpha.-acyloxyalkyl ethers include
acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of
in vivo hydrolysable ester forming groups for hydroxyl include
alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and
phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters),
dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to
give carbamates), dialkylaminoacetyl and carboxyacetyl.
[0282] The compounds of the present invention according to Formula
(I) and salts, solvates, N-oxides and prodrugs thereof may contain
one or more asymmetric centers. Asymmetric carbon atoms may be
present in the (R) or (S) configuration or (R,S) configuration.
Substituents on a ring may also be present in either cis or trans
form. It is intended that all such configurations (including
enantiomers and diastereomers), are included within the scope of
the present invention. Preferred stereoisomers are those with the
configuration which produces the more desirable biological
activity. Separated, pure or partially purified configurational
isomers or racemic mixtures of the compounds of this invention are
also included within the scope of the present invention. The
purification of said isomers and the separation of said isomeric
mixtures can be accomplished by standard techniques known in the
art.
[0283] Another embodiment of the present invention relates to the
use of a compound of general formula (11) as mentioned below for
the preparation of a compound of general formula (I) as defined
supra.
[0284] Yet another embodiment of the present invention relates to
the use of a compound of general formula (1) as mentioned below for
the preparation of a compound of general formula (I) as defined
supra, further to the use of a compound of general formula (1) as
mentioned below for the preparation of a compound of general
formula (Ia) as mentioned below.
[0285] Yet another embodiment of the present invention relates to
the use of a compound of general formula (3) as mentioned below for
the preparation of a compound of general formula (I) as defined
supra.
[0286] Another embodiment of the present invention relates to the
use of a compound of general formula (12) as mentioned below for
the preparation of a compound of general formula (I) as defined
supra, further to the use of a compound of general formula (12) as
mentioned below for the preparation of a compound of general
formula (Ia) as mentioned below.
[0287] Another embodiment of the present invention relates to the
use of a compound of general formula (14) as mentioned below for
the preparation of a compound of general formula (I) as defined
supra, further to the use of a compound of general formula (14) as
mentioned below for the preparation of a compound of general
formula (Ia) as mentioned below.
[0288] The compounds of the present invention can be used in
treating diseases of dysregulated vascular growth or diseases which
are accompanied with dysregulated vascular growth. Especially, the
compounds effectively interfere with cellular Tie2 signalling. The
compounds of the present invention are selective inhibitors of Tie2
kinase activity vs. InsR kinase activity.
[0289] Therefore, another aspect of the present invention is a use
of the compound of general formula (I) described supra for
manufacturing a pharmaceutical composition for the treatment of
diseases of dysregulated vascular growth or of diseases which are
accompanied with dysregulated vascular growth.
[0290] In particular, said use is in the treatment of diseases,
wherein the diseases are tumors and/or metastases thereof. The
compounds of the present invention can be used in particular in
therapy and prevention of tumor growth and metastases, especially
in solid tumors of all indications and stages with or without
pre-treatment if the tumor growth is accompanied with persistent
angiogenesis, principally including all solid tumors, e.g. breast,
colon, renal, ovarian, prostate, thyroid, lung and/or brain tumors,
melanoma, or metastases thereof.
[0291] Additionally, said use is in the treatment of chronic
myelogeneous leukaemia (or "CML"), acute myelogenous leukaemia (or
"AML"), acute lymphatic leukaemia, acute lymphocytic leukaemia (or
"ALL"), chronic lymphocytic leukaemia, chronic lymphatic leukaemia
(or "CLL") as well as other myeloid precursor hyperplasias such as
polycythemia vera and myelofibrosis.
[0292] Another use is in the treatment of diseases, wherein the
diseases are retinopathy, other angiogenesis dependent diseases of
the eye, in particular cornea transplant rejection or age-related
macular degeneration.
[0293] Yet another use is in the treatment of rheumatoid arthritis,
and other inflammatory diseases associated with angiogenesis, in
particular psoriasis, delayed type hypersensitivity, contact
dermatitis, asthma, multiple sclerosis, restenosis, pulmonary
hypertension, stroke, and inflammatory diseases of the bowel, such
as, for example, Crohn's disease.
[0294] A further use is in the suppression of the development of
atherosclerotic plaque formation and for the treatment of coronary
and peripheral artery disease.
[0295] Another use is in the treatment of diseases associated with
stromal proliferation or characterized by pathological stromal
reactions and for the treatment of diseases associated with
deposition of fibrin or extracellular matrix, such as, for example,
fibrosis, cirrhosis, carpal tunnel syndrome.
[0296] Yet another use is in the treatment of gynaecological
diseases where inhibition of angiogenic, inflammatory and stromal
processes with pathological character can be inhibited, such as,
for example, endometriosis, pre-eclampsia, postmenopausal bleeding
and ovarian hyperstimulation.
[0297] Another use is in the treatment of diseases, wherein the
diseases are ascites, oedema such as brain tumor associated oedema,
high altitude trauma, hypoxia induced cerebral oedema, pulmonary
oedema and macular oedema or oedema following burns and trauma,
chronic lung disease, adult respiratory distress syndrome, bone
resorption and for the treatment of benign proliferating diseases
such as myoma, benign prostate hyperplasia.
[0298] A further use is in wound healing for the reduction of scar
formation, and for the reduction of scar formation during
regeneration of damaged nerves.
[0299] Yet another aspect of the invention is a method of treating
a disease of dysregulated vascular growth or diseases which are
accompanied with dysregulated vascular growth, by administering an
effective amount of a compound of general formula (I) described
supra.
[0300] In particular, the diseases of said method are tumors and/or
metastases thereof, in particular solid tumors of all indications
and stages with or without pre-treatment if the tumor growth is
accompanied with persistent angiogenesis, principally including all
solid tumors, e.g. breast, colon, renal, ovarian, prostate,
thyroid, lung and/or brain tumors, melanoma, or metastases
thereof.
[0301] Additionally, diseases of said method are chronic
myelogeneous leukaemia (or "CML"), acute myelogenous leukaemia (or
"AML"), acute lymphatic leukaemia, acute lymphocytic leukaemia (or
"ALL"), chronic lymphocytic leukaemia, chronic lymphatic leukaemia
(or "CLL") as well as other myeloid precursor hyperplasias such as
polycythemia vera and myelofibrosis.
[0302] Further diseases of said method are retinopathy, other
angiogenesis dependent diseases of the eye, in particular cornea
transplant rejection or age-related macular degeneration.
[0303] Further diseases of said method are rheumatoid arthritis,
and other inflammatory diseases associated with angiogenesis, in
particular psoriasis, delayed type hypersensitivity, contact
dermatitis, asthma, multiple sclerosis, restenosis, pulmonary
hypertension, stroke, and inflammatory diseases of the bowel, such
as, for example, Crohn's disease.
[0304] Further diseases of said method are the development of
atherosclerotic plaques and coronary and peripheral artery
diseases.
[0305] Further diseases of said method are diseases associated with
stromal proliferation or characterized by pathological stromal
reactions and diseases associated with deposition of fibrin or
extracellular matrix, such as, for example, fibrosis, cirrhosis,
carpal tunnel syndrome.
[0306] Further diseases of said method are gynaecological diseases
where inhibition of angiogenic, inflammatory and stromal processes
with pathological character can be inhibited, such as, for example,
endometriosis, pre-eclampsia, postmenopausal bleeding and ovarian
hyperstimulation.
[0307] Further diseases of said method are ascites, oedema such as
brain tumor associated oedema, high altitude trauma, hypoxia
induced cerebral oedema, pulmonary oedema and macular oedema or
oedema following burns and trauma, chronic lung disease, adult
respiratory distress syndrome, bone resorption and benign
proliferating diseases such as myoma, benign prostate
hyperplasia.
[0308] Another aspect of the present invention is a pharmaceutical
composition which comprises a compound of general formula (I) as
defined above, or as obtainable by a method described in this
invention, or a pharmaceutically acceptable salt or an N-oxide or a
solvate or a prodrug of said compound, and a pharmaceutically
acceptable diluent or carrier, the composition being particularly
suited for the treatment of diseases of dysregulated vascular
growth or of diseases which are accompanied with dysregulated
vascular growth as explained above.
[0309] In order to use the compounds of the present invention as
pharmaceutical products, the compounds or mixtures thereof may be
provided in a pharmaceutical composition, which, as well as the
compounds of the present invention for enteral, oral or parenteral
application contains suitable pharmaceutically acceptable organic
or inorganic inert base material, e.g. purified water, gelatine,
gum Arabic, lactate, starch, magnesium stearate, talcum, vegetable
oils, polyalkyleneglycol, etc.
[0310] The pharmaceutical compositions of the present invention may
be provided in a solid form, e.g. as tablets, dragees,
suppositories, capsules or in liquid form, e.g. as a solution,
suspension or emulsion. The pharmaceutical composition may
additionally contain auxiliary substances, e.g. preservatives,
stabilisers, wetting agents or emulsifiers, salts for adjusting the
osmotic pressure or buffers.
[0311] For parenteral applications, (including intravenous,
subcutaneous, intramuscular, intravascular or infusion), sterile
injection solutions or suspensions are preferred, especially
aqueous solutions of the compounds in polyhydroxyethoxy containing
castor oil.
[0312] The pharmaceutical compositions of the present invention may
further contain surface active agents, e.g. salts of gallenic acid,
phospholipids of animal or vegetable origin, mixtures thereof and
liposomes and parts thereof.
[0313] For oral application tablets, dragees or capsules with
talcum and/or hydrocarbon-containing carriers and binders, e.g.
lactose, maize and potato starch, are preferred. Further
application in liquid form is possible, for example as juice, which
contains sweetener if necessary.
[0314] The dosage will necessarily be varied depending upon the
route of administration, age, weight of the patient, the kind and
severity of the illness being treated and similar factors. A dose
can be administered as unit dose or in part thereof and distributed
over the day. Accordingly the optimum dosage may be determined by
the practitioner who is treating any particular patient.
[0315] It is possible for compounds of general formula (I) of the
present invention to be used alone or, indeed in combination with
one or more further drugs, particularly anti-cancer drugs or
compositions thereof. Particularly, it is possible for said
combination to be a single pharmaceutical composition entity, e.g.
a single pharmaceutical formulation containing one or more
compounds according to general formula (I) together with one or
more further drugs, particularly anti-cancer drugs, or in a form,
e.g. a "kit of parts", which comprises, for example, a first
distinct part which contains one or more compounds according to
general formula (I), and one or more further distinct parts each
containing one or more further drugs, particularly anti-cancer
drugs. More particularly, said first distinct part may be used
concomitantly with said one or more further distinct parts, or
sequentially. In addition, it is possible for compounds of general
formula (I) of the present invention to be used in combination with
other treatment paradigms, particularly other anti-cancer treatment
paradigms, such as, for example, radiation therapy.
[0316] Another aspect of the present invention is a method which
may be used for preparing the compounds according to the present
invention.
Experimental Details and General Processes
[0317] The following table lists the abbreviations used in this
paragraph and in the Examples section as far as they are not
explained within the text body. NMR peak forms are stated as they
appear in the spectra, possible higher order effects have not been
considered. Assignments of substitution degrees (e.g. CH.sub.3,
CH.sub.2, CH or Cq signals) of carbon atoms in .sup.13C-NMR spectra
are based on .sup.13C-DEPT NMR analysis. Chemical names were
generated using AutoNom2000 as implemented in MDL ISIS Draw. In
some cases generally accepted names of commercially available
reagents were used in place of AutoNom2000 generated names. The
compounds and intermediates produced according to the methods of
the invention may require purification. Purification of organic
compounds is well known to the person skilled in the art and there
may be several ways of purifying the same compound. In some cases,
no purification may be necessary. In some cases, the compounds may
be purified by crystallization. In some cases, impurities may be
stirred out using a suitable solvent. In some cases, the compounds
may be purified by chromatography, particularly flash column
chromatography, using for example prepacked silica gel cartridges,
e.g. from Separtis such as Isolute.RTM. Flash silica gel or
Isolute.RTM. Flash NH.sub.2 silica gel in combination with a
Flashmaster II autopurifier (Argonaut/Biotage) and eluents such as
gradients of hexane/EtOAc or DCM/ethanol. In some cases, the
compounds may be purified by preparative HPLC using for example a
Waters autopurifier equipped with a diode array detector and/or
on-line electrospray ionization mass spectrometer in combination
with a suitable prepacked reverse phase column and eluents such as
gradients of water and acetonitrile which may contain additives
such as trifluoroacetic acid or aqueous ammonia. In some cases,
purification methods as described above can provide those compounds
of the present invention which possess a sufficiently basic or
acidic functionality in the form of a salt, such as, in the case of
a compound of the present invention which is sufficiently basic, a
trifluoroacetate or formate salt for example, or, in the case of a
compound of the present invention which is sufficiently acidic, an
ammonium salt for example. A salt of this type can either be
transformed into its free base or free acid form, respectively, by
various methods known to the person skilled in the art, or be used
as salts in subsequent biological assays. It is to be understood
that the specific form (e.g. salt, free base . . . ) of a compound
of the present invention as isolated as described herein is not
necessarily the only form in which said compound can be applied to
a biological assay in order to quantify the specific biological
activity. Reactions employing microwave irradiation may be run with
a Biotage Initator.RTM. microwave oven optionally equipped with a
robotic unit. The reported reaction times employing microwave
heating are intended to be understood as fixed reaction times after
reaching the indicated reaction temperature.
TABLE-US-00001 Abbreviation Meaning Ac Acetyl Boc
tert-butyloxycarbonyl br Broad CI chemical ionisation d Doublet dd
doublet of doublet DCM Dichloromethane DIPEA N,N-diisopropylethyl
amine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide eq.
Equivalent ESI electrospray ionisation GP general procedure HPLC
high performance liquid chromatography LC-MS Liquid chromatography
mass spectrometry m Multiplet mc centred multiplet MS mass
spectrometry NMR nuclear magnetic resonance spectroscopy: chemical
shifts (.delta.) are given in ppm. Pg protecting group q Quartet rf
at reflux r.t. or rt room temperature s Singlet sept. Septet t
Triplet TEA Triethylamine TFA trifluoroacetic acid THF
Tetrahydrofuran
[0318] The following schemes and general procedures illustrate
general synthetic routes to the compounds of general formula I of
the invention and are not intended to be limiting. It is obvious to
the person skilled in the art that the order of transformations as
exemplified in Schemes 1 to 8 can be modified in various ways. The
order of transformations exemplified in Schemes 1 to 8 is therefore
not intended to be limiting. In addition, interconversion of
substituents, for example of residues R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.a, R.sup.b, R.sup.c, R.sup.d1, R.sup.d2 and
R.sup.d3 can be achieved before and/or after the exemplified
transformations. These modifications can be such as the
introduction of protecting groups, cleavage of protecting groups,
reduction or oxidation of functional groups, halogenation,
metallation, substitution or other reactions known to the person
skilled in the art. These transformations include those which
introduce a functionality which allows for further interconversion
of substituents. Appropriate protecting groups and their
introduction and cleavage are well-known to the person skilled in
the art (see for example T. W. Greene and P. G. M. Wuts in
Protective Groups in Organic Synthesis, 3.sup.rd edition, Wiley
1999).
##STR00004##
[0319] Compounds of general formula (I) can be synthesized
according to the procedure depicted in Scheme 1 from amines of
general formula 1 by reaction with, for example, a suitably
functionalized isocyanate (leading to ureas), a suitably
functionalized sulfonyl chloride (leading to sulfonyl amides) or a
suitably functionalized acid chloride (leading to carboxylic
amides), in the presence of a suitable base as necessary, e.g.
pyridine or triethylamine, which may also be used as solvent,
optionally in the presence of an inert solvent, e.g.
dichloromethane, acetonitrile, DMF or THF, at temperatures ranging
from -20.degree. C. to the boiling point of the solvent, whereby
room temperature is preferred.
[0320] A variety of suitable isocyanates for the above described
transformation is described in the literature or commercially
available. The person skilled in the art is well aware of
alternative methods of forming ureas, which may be of special
importance in cases were the respective isocyanates are not readily
available (see Schemes 2, 2b, 2c for exemplary, more specific
urea-forming processes).
[0321] Processes for the preparation of functionalized (hetero)aryl
sulfonyl chlorides are as well known to the person skilled in the
art. Introduction of sulfonyl groups may be accomplished by
sulfonylation or by oxidation of thiols. Sulfonyl chlorides may be
accessible in turn from sulfonic acids by reaction with e.g.
thionyl chloride, sulfuryl chloride, PCl.sub.5, POCl.sub.3 or
oxalyl chloride.
[0322] In the case of the transformation of amines of general
formula 1 into amides of general formula I [with A being --C(O)--],
it is also possible to react amines of general formula 1 with an
appropriate ester according to a method described in J. Org. Chem.
1995, 8414 in the presence of trimethylaluminium and in suitable
solvents such as toluene, at temperatures of 0.degree. C. to the
boiling point of the solvent. For amide formations, however, all
processes that are known from peptide chemistry to the person
skilled in the art are also available. For example, the
corresponding acid, which may be obtained from the corresponding
ester by saponification, can be reacted with amines of general
formula 1 in aprotic polar solvents, such as, for example, DMF, via
an activated acid derivative, which is obtainable, for example,
with hydroxybenzotriazole and a carbodiimide, such as, for example,
diisopropylcarbodiimide (DIC), at temperatures of between 0.degree.
C. and the boiling point of the solvent, preferably at 80.degree.
C., or else with preformed reagents, such as, for example,
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU) (see for example Chem. Comm. 1994, 201),
at temperatures of between 0.degree. C. and the boiling point of
the solvent, preferably at room temperature, or else with
activating agents such as dicyclohexylcarbodiimide
(DCC)/dimethylaminopyridine (DMAP) or
N-ethyl-N'-dimethylaminopropylcarbodiimide
(EDCI)/dimethylaminopyridine (DMAP) or T3P (1-propanephosphoric
acid cyclic anhydride). The addition of a suitable base such as,
for example, N-methylmorpholine, TEA, DIPEA may be necessary. Amide
formation may also be accomplished via the acid halide (which can
be formed from a carboxylic acid by reaction with e.g. oxalyl
chloride, thionyl chloride or sulfuryl chloride), mixed acid
anhydride (which can be formed from a carboxylic acid by reaction
with e.g. isobutyrochloroformiate), imidazolide (which can be
formed from a carboxylic acid by reaction with e.g.
carbonyldiimidazolide) or azide (which can be formed from a
carboxylic acid by reaction with e.g. diphenylphosphorylazide
DPPA).
[0323] The carboxylic acids required for the above described amide
coupling reactions are either commercially available or are
accessible from commercially available carboxylic esters or
nitrites. Alternatively, (hetero)aryls bearing a methylenenitrile
substituent are easily accessible from the respective halides via a
nucleophilic substitution reaction (e.g. KCN, cat. KI,
EtOH/H.sub.2O). Incorporation of additional functionality into
commercially available starting materials can be accomplished by a
multitude of aromatic transformation reactions known to the person
skilled in the art, including, but not limited to, electrophilic
halogenations, electrophilic nitrations, Friedel-Crafts acylations,
nucleophilic displacement of fluorine by oxygen nucleophiles and
transformation of (hetero)aryl carboxylic acids into amides and
subsequent reduction into benzylic amines, whereby the latter two
methods are of particular relevance for the introduction of ether
and/or aminomethylene side chains.
[0324] Benzylic nitrites and esters (and heteroaryl analogs
thereof) can be efficiently alkylated at the benzylic position
under basic conditions and subsequently hydrolyzed to the
corresponding alkylated acids. Conditions for .alpha.-alkylations
of nitrites and esters include, but are not limited to, the use of
alkyl bromides or alkyl iodides as electrophiles under basic
conditions in the presence or absence of a phase-transfer catalyst
in a mono- or biphasic solvent system. Particularly, by using
excess alkyl iodides as electrophilic species
.alpha.,.alpha.-dialkylated nitrites are accessible. More
particularly, by using 1,.omega.-dihaloalkyls as electrophiles
cycloalkyl moieties can be installed at the benzylic position of
nitrites and esters (J. Med. Chem. 1975, 18, 144; WO2003022852).
Even more particularly, by using a 1,2-dihaloethane, such as, for
example, 1,2-dibromoethane or 1-bromo-2-chloroethane, a
cyclopropane ring can be installed at the benzylic position of a
nitrite or ester. The hydrolysis of nitrites to yield carboxylic
acids can be accomplished, as known to the person skilled in the
art, under acid or base-mediated conditions.
##STR00005##
[0325] An alternative, more specific process of generating ureas of
general formula Ia is depicted in Scheme 2. In this case, urea
formation starting from amines of general formula 1 may be achieved
by coupling with a second functionalized amine of general formula 2
via in situ transformation of one of the reacting amines into the
respective carbamoyl chloride, aryl- or alkenylcarbamate (see for
example J. Org. Chem. 2005, 70, 6960 and references cited therein).
This process may provide an alternative to the formation and
isolation of the respective isocyanate derived from one of the
starting amines (see for example Tetrahedron Lett. 2004, 45, 4769).
More particularly, ureas of formula Ia may be formed from two
suitably functionalized amines and a suitable phosgene equivalent,
preferably triphosgene, in an inert solvent, preferably
acetonitrile, at temperatures ranging from -20.degree. C. to the
boiling point of the solvent, whereby room temperature is
preferred.
##STR00006## ##STR00007##
[0326] The aforementioned alternative procedure for generating
ureas of general formula Ia employing alkenylcarbamates, for
example isopropenylcarbamates, is depicted in more detail in Scheme
2b. In analogy to the aforecited publication (J. Org. Chem. 2005,
70, 6960) transformation of amines of general formula 1 into their
respective isopropenyl carbamates of general formula 12 can be
accomplished by reaction with isopropenyl chloro formate in the
presence of an appropriate base, such as, for example,
N-methylmorpholine, in a suitable solvent, such as, for example,
THF. Isopropenyl carbamates of general formula 12 can then be
reacted, after isolation or in situ, with (hetero)aryl amines of
general formula 2 in the presence of a suitable base, such as, for
example, N-methylpyrrolidine, in a suitable solvent, such as, for
example THF, to yield ureas of general formula Ia. Alternatively,
(hetero)aryl amines of general formula 2 can be transformed into
their corresponding isopropenyl carbamates of general formula 13
employing condition as described above and subsequently reacted
with amines of general formula 1 under conditions as described
above to yield ureas of general formula Ia.
##STR00008## ##STR00009##
[0327] An additional method for generating ureas of general formula
Ia employing aryl carbamates, for example phenyl carbamates or
4-NO.sub.2-phenyl carbamates in analogy to procedures described for
example in WO2007064872 or WO2005110994, is exemplified in Scheme
2c. Transformation of amines of general formula 1 into their
respective phenyl carbamates of general formula 14 can be
accomplished by reaction with phenyl chloro formate in the presence
of an appropriate base, such as, for example, sodium carbonate, in
a suitable solvent, such as, for example, THF. Phenyl carbamates of
general formula 14 can then be reacted, after isolation or in situ,
with (hetero)aryl amines of general formula 2 in the presence of a
suitable base, such as, for example, pyridine, in a suitable
solvent, such as, for example THF, to yield ureas of general
formula Ia. Alternatively, (hetero)aryl amines of general formula 2
can be transformed into their corresponding phenyl carbamates of
general formula 15 employing condition as described above and
subsequently reacted with amines of general formula 1 under
conditions as described above to yield ureas of general formula
Ia.
[0328] Processes for the preparation of functionalized (hetero)aryl
amines as coupling partners for the above described transformation
are well known to the person skilled in the art. Starting from
commercially available (hetero)aryl amines or nitro(hetero)arylenes
well known transformations, including, but not limited to,
alkylations, nucleophilic or electrophilic substitutions,
acylations, halogenations, nitrations, sulfonylations, (transition)
metal catalyzed couplings, metallations, rearrangements,
reductions, and/or oxidations may be applied to prepare
functionalized amines to be used in the urea formation step. In
addition to specific procedures given in the following experimental
section, detailed procedures may be found in the scientific and
patent literature (see for example WO2005051366, WO2005110410,
WO2005113494, WO2006044823, and WO2006124462; WO2007064872 and
WO2005110994).
##STR00010##
[0329] A reaction sequence for the preparation of especially
suitable (hetero)aryl amines for the above described urea formation
processes is depicted in Scheme 2d. (Hetero)aryl carboxylic acids
of general formula 16 can be reduced to benzylic alcohols of
general formula 17 under standard conditions as known to the person
skilled in the art, for example, by reaction with borane-THF
complex or NaBH.sub.4/I.sub.2. Bromination of benzylic alcohols of
general formula 17 leading to benzylic bromides of general formula
18 is feasible employing, for example, CBr.sub.4 in the presence of
triphenylphosphine. Reaction of benzylic bromides of general
formula 18 with amines of general formula 19 gives rise to benzylic
amines of general formula 20 which can subsequently be reduced
under standard conditions as known to the person skilled in the
art, for example, by Pd-catalyzed hydrogenation or by reaction with
SnCl.sub.2, into amines of general formula 2'.
##STR00011##
[0330] Further reaction sequences for the preparation of especially
suitable (hetero)aryl amines for the above described urea formation
processes are depicted in Scheme 2e. (Hetero)aryl fluorides of
general formula 21 are reacted with amines of general formula 19 in
a nucleophilic aromatic substitution reaction in the presence of a
suitable base, such as, for example, NaHCO.sub.3, in a suitable
solvent such as, for example, DMF, under heating, optionally by
microwave irradiation, to form anilines of general formula 22.
Alternatively, reaction with alcohols of general formula 23 in the
presence of a suitable base, such as, for example, cesium
carbonate, optionally under heating, gives rise to nitro ethers of
general formula 24. Subsequent nitro reduction leads to amines of
general formula 2'' or general formula 2''', respectively.
##STR00012##
[0331] Amines of general formula 1 are accessible, for example, by
transition metal-catalyzed coupling of an appropriate
4-halopyrazolopyridine of general formula 3 with boronic acids or
their respective esters of general formula 4. More particularly,
amines of formula 1 can be prepared starting from a halogenated
pyrazolopyridine 3 by Pd-catalyzed Suzuki-type coupling reactions
with (hetero)aryl boronic acids 4 or even more particularly with
their respective boronate esters (e.g. a pinacolate ester).
Transition metal-catalyzed couplings of heteroaryl halides with
(hetero)aryl boronic acids or (hetero)aryl boronate esters are well
known to the person skilled in the art. Various
catalyst/ligand/base/solvent combinations have been published in
the scientific literature (see for example Tetrahedron 2005, 61,
5131 and references cited therein; Eur. J. Org. Chem. 2006, 1917
and references cited therein; Eur. J. Org. Chem. 2006, 2063 and
references cited therein), which allow a fine-tuning of the
required reaction conditions in order to allow for a broad set of
additional functional groups on both coupling partners.
Alternatively, the boronic acids of general formula 4 may be
replaced by, for example, a suitably substituted trifluoroboronate
salt or a suitably substituted stannane. Conditions for Stille-type
couplings of aryl- or heteroaryl stannanes to aryl or heteroaryl
halides employing a Pd catalyst and optionally a mediator are well
known to the person skilled in the art. In some cases introduction
of an amine protecting group may facilitate the coupling reaction
exemplified in Scheme 3. Appropriate protecting groups and their
introduction and cleavage are well-known to the person skilled in
the art (see for example T. W. Greene and P. G. M. Wuts in
Protective Groups in Organic Synthesis, 3.sup.rd edition, Wiley
1999). Alternatively, the amino group in the coupling partner 4 can
be replaced by a nitro group which is reduced to the corresponding
amino group subsequent to the coupling reaction.
##STR00013##
[0332] A more convergent alternative to the process exemplified
before is depicted in Scheme 4, in which compounds of the present
invention of general formula I are prepared by a transition metal
catalyzed coupling of an appropriate halo precursor of general
formula 3 and appropriately substituted boronic acids or boronate
esters of general formula 5. More particularly, compounds of the
present invention can be prepared starting from a halogenated
pyrazolopyridine 3 by Pd-catalyzed Suzuki-type coupling reactions
with (hetero)aryl boronic acids 5 or even more particularly with
their respective boronate esters (e.g. a pinacolate ester).
Functionalized boronic acids and their respective pinacolate esters
of general formula 5 can be prepared e.g. by urea formation or
sulphonamide formation or amide coupling of accordingly substituted
anilines (e.g. of general formula 4). In addition, boronic acids or
boronate esters can be introduced into aryl or heteroaryl compounds
inter alia by substituting halogen atoms. This substitution can be
accomplished by metallation followed by electrophilic borylation
(Org. Biomol. Chem. 2004, 2, 852) or by direct Pd- or Cu-catalyzed
borylation (Synlett 2003, 1204 and references cited therein; Org.
Lett. 2006, 8, 261). Interconversion of boronic acids into the
respective esters (e.g. their pinacolate esters) can be
accomplished under standard conditions (for example by treatment
with pinacol in EtOH at r.t.).
##STR00014##
[0333] Compounds of general formula I' with R.sup.1.noteq.H (Scheme
5) are accessible from precursors of general formula 1 or 3 (with
R.sup.1.noteq.H) by, for example, the aforementioned
transformations. Alternatively, as depicted in Scheme 5, compounds
of general formula I' with R.sup.1.noteq.H are accessible from the
respective 1H-pyrazolopyridines of general formula Ib by, for
example, alkylation or acylation reactions and subsequent
transformations. This process is of particular importance if
appropriately substituted hydrazines are not readily available (see
below). Introduction of R.sup.1-groups can be achieved employing
various conditions for introducing substituents to nitrogen atoms
as known to the person skilled in the art. These conditions
include, but are not limited to, alkylations under basic conditions
employing alkyl-, allyl-, benzylhalides or .alpha.-halocarbonyl
compounds as electrophiles (e.g. WO2005056532; Chem. Pharm. Bull.
1987, 35, 2292; J. Med. Chem. 2005, 48, 6843), alkylations under
reductive conditions employing aldehydes as electrophiles and an
appropriate reducing agent (e.g. BH.sub.3.pyr, NaBH(OAc).sub.3,
NaBH.sub.3CN, NaBH.sub.4), Mitsunobu-type alkylations employing
primary or secondary alcohols as electrophiles (e.g. Tetrahedron
2006, 62, 1295; Bioorg. Med. Chem. Lett. 2002, 12, 1687), or
N-acylations (see for example J. Med. Chem. 2005, 48, 6843)
optionally followed by amide reduction.
##STR00015##
[0334] Halides of general formula 3 are accessible, for example, as
depicted in Scheme 6, from carbaldehydes of general formula 6 by
transformation into hydrazones of formula 7 and subsequent
cyclization. It is to be understood that hydrazone formation and
cyclization can be accomplished in one preparative transformation
or, alternatively, in two separate steps. More particularly,
carbaldehydes of formula 6 can be reacted with hydrazine (e.g.
hydrazine hydrate) or substituted hydrazines in an appropriate
solvent, preferably in 1-PrOH, at an appropriate temperature,
preferably at 100 to 120.degree. C., to yield hydrazones of formula
7 or halopyrazolopyridines of formula 3. Isolated hydrazones of
formula 7 can be cyclized to halopyrazolopyridines of formula 3
e.g. by applying basic conditions, preferably by reacting with
sodium hydride, in an appropriate solvent, preferably DMF. A
variety of substituted hydrazine building blocks required for the
conversion of pyridines of formula 6 into intermediates of formula
7 and/or 3 is commercially available, either in form of their free
base or as various types of salts (e.g. hydrochlorides, oxalates),
which can be transformed into their respective free bases by
alkaline treatment either before the cyclization or in situ.
Additionally, substituted alkyl-, allyl-, and benzylhydrazines (or
their respective hydrochloride salts) are accessible from the
respective alkyl-, allyl- and benzylhalides, preferably the
respective alkyl-, allyl- and benzylbromides, by nucleophilic
substitution reaction with a protected hydrazine, such as
BocNHNH.sub.2, in an inert solvent, preferably MeOH, in the
presence of an amine promoter, e.g. Et.sub.3N, at temperatures
ranging from room temperature up to the boiling point of the
solvent, optionally followed by deprotection employing conditions
known to the person skilled in the art, preferably, in the case of
Boc deprotection, by treatment with HCl in a mixture of diethyl
ether and methanol (for a representative procedure, see J. Med.
Chem. 2006, 49, 2170). As an alternative to the use of hydrazine
hydrate in the transformation exemplified in Scheme 6, protected
analogues, e.g. Boc-hydrazine (also known as tert-butyl carbazate),
benzyl hydrazine or para-methoxybenzyl hydrazine can be used
instead. Removal of the respective protecting group is feasible by
standard transformations as known to the person skilled in the art,
e.g. by hydrogenation, acid treatment or base treatment.
Carbaldeyhdes of general formula 6 are either commercially
available or can be synthesized, for example, from the respective
dihalopyridines by formylation reactions, more particularly, by
metallation followed by formylation of the respective metallated
species (see for example Tetrahedron Lett. 1996, 37, 2565, U.S.
Pat. No. 6,232,320 or WO2005110410).
[0335] As stated above, the order of transformations as exemplified
in Scheme 4 and 6 is not intended to be limiting. For example,
3,5-dihalopyridine carbaldehydes of formula 6 can also be
cross-coupled with an appropriately substituted boronic acid or
boronic acid ester, for example of formula 4 or 5, followed by
pyrazolopyridine formation by reaction with, for example, hydrazine
hydrate or a substituted hydrazine to yield compounds of formula 1
or I.
[0336] The respective R.sup.2 substituent of compounds of the
present invention of general formula I can be present in any of the
afore- and below-mentioned synthetic intermediates or starting
materials. Alternatively, a R.sup.2 substituent can be introduced
before or after any of the afore- or below-mentioned processes. One
particular process for the introduction of R.sup.2 substituents is
exemplified in the following scheme and paragraph (Scheme 7). It is
to be understood, that this process is not limited to the
exemplified starting material, but can be applied to other
commercially available pyridine starting materials or synthetic
intermediates of processes exemplified in this application.
##STR00016##
[0337] Functionalization of the position adjacent to the pyridine
nitrogen, for example of the C5- or C7-position of
pyrazolopyridines of general formula 8, or alternatively of
pyridine-containing synthetic intermediates exemplified in Schemes
1 to 6, is feasible, for example, via formation of the
corresponding N-oxide of general formula 9. Transformation of
pyridines into pyridine N-oxides can be accomplished by various
ways, preferably by reaction with an oxidizing reagent, such as,
for example, meta-chloroperbenzoic acid. Pyridine N-oxides of
general formula 9 can be rearranged to 5-chloro and/or
7-chloropyrazolopyridines (general formula 10 with R.sup.2=Cl) by
reaction with, for example, phosphoroxychloride or methyl
chloroformiate in the presence of hexamethyldisilazane (see for
example WO2005058891). Reaction of pyridine N-oxides with, for
example, phosphoroxychloride can lead to regioisomeric product
mixtures, which can be separated by standard purification
procedures. 5-Chloro- and/or 7-chloropyrazolopyridines allow for
various subsequent transformations, for example nucleophilic
displacements with amines or alcohols, transition metal-catalyzed
cross coupling reactions or metallations followed by reactions with
electrophiles. Alternatively, pyridine N-oxides of general formula
9 can be reacted with acetic anhydride to yield the respective 5-
and/or 7-acetoxypyrazolopyridines resulting from the so-called
Boekelheide rearrangement. Other processes are known to the person
skilled in the art which allow for introducing a substituent into
pyridine N-oxides (see for example Keith, J. M. J. Org. Chem. 2006,
71, 9540), inter alia transition metal catalyzed cross-coupling
reactions (see for example Campeau, L.-C. et al. J. Am. Chem. Soc.
2005, 127, 18020).
##STR00017##
[0338] In addition to the processes described in the preceding
schemes and paragraphs, compounds of the present invention of
general formula I can be prepared from the corresponding
3-aminopyrazolopyridines of general formula 11. Desamination of
3-aminopyrazolopyridines of formula 11 is feasible, for example, by
reaction with sodium nitrite followed by heating in the presence of
an acid, such as, for example, sulphuric acid. In analogy to the
process depicted in Scheme 8, compounds of e.g. formula Ia, Ib, 1,
3, 8 and 10 are accessible from the corresponding
3-aminopyrazolopyridines by deamination as described above. The
respective 3-aminopyrazolopyridines can be prepared in analogy to
the described processes by substituting starting material 6 (Scheme
6) with the respective 3,5-dihalo-5-cyanopyridine, which in turn
can be prepared as described in the literature.
General Procedures
[0339] In the subsequent paragraphs detailed general procedures for
the synthesis of key intermediates and compounds of the present
invention are described.
General Procedure 1 (GP 1): Hydrazone Formation
[0340] The respective heteroaryl carbaldehyde was dissolved in
1-PrOH (.about.4-5 mL per mmol carbaldehyde), treated with the
respective hydrazine (1.5-3.0 eq.) and subsequently heated to
100-120.degree. C. in a microwave oven (Biotage Initiator.RTM.).
The reaction mixture was concentrated, the residue partitioned
between water and ethyl acetate, the aqueous layer reextracted with
ethyl acetate, the combined organic layers dried and concentrated
in vacuo to yield the desired product, which was typically used in
the subsequent cyclization without further purification steps.
General Procedure 2 (GP 2): Hydrazone Cyclization
[0341] The respective hydrazone (prepared as described in GP 1) was
dissolved in dry THF (.about.9 mL per mmol hydrazone), treated with
50-60% NaH (1.2 to 2.2 eq.) and subsequently refluxed for 90 min.
The reaction mixture was quenched with water, extracted with ethyl
acetate, the combined organic layers dried and concentrated in
vacuo. The precipitate was filtered and subsequently triturated
with diisopropylether to yield the desired product. Flash column
chromatography of the mother liquor provided a second batch of the
analytically pure product. Alternatively, in most cases
concentration of the crude reaction mixture to dryness provided the
cyclized product in sufficient purity for subsequent
transformations.
General Procedure 3 (GP 3): Suzuki Coupling (Conditions A)
[0342] The heteroaryl halide (1 eq), the respective aryl pinacolato
boronate or aryl boronic acid (1.2 to 1.8 eq.) and
Pd(PPh.sub.3).sub.4 (6 mol %) were weighed into a Biotage microwave
vial and capped. Toluene (6 mL per mmol halide), EtOH (6 mL per
mmol halide) and 1M aq. Na.sub.2CO.sub.3 solution (2 eq.) were
added by syringe. The resulting mixture was prestirred (10 sec) and
subsequently heated to 100-120.degree. C. for 15 min (fixed hold
time) in a Biotage Initiator.RTM. microwave reactor. The reaction
mixture was diluted with water and ethyl acetate, the layers were
separated and the aqueous layer extracted with ethyl acetate. The
combined organic layers were dried and concentrated in vacuo. The
residue was optionally purified by flash column chromatography
and/or trituration and/or preparative HPLC.
General Procedure 4 (GP 4): Suzuki Coupling (Conditions B)
[0343] The heteroaryl halide (1 eq), the respective aryl pinacolato
boronate or aryl boronic acid (1.2 to 1.5 eq.) and FibreCat 1032
(Johnson-Matthey; 0.38 mmol/g loading; 6 mol %) were weighed into a
Biotage microwave vial and capped. EtOH (.about.9 mL per mmol
halide) and 1M aq. K.sub.2CO.sub.3 solution (1.5 eq.) were added by
syringe. The resulting mixture was prestirred (10 sec) and
subsequently heated to 100-130.degree. C. for 20 min in a Biotage
Initiator.RTM. microwave oven. After filtration and concentration
in vacuo, the residue was taken up in ethyl acetate and water was
added, the layers were separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
dried and concentrated in vacuo. The residue was optionally
purified by flash column chromatography and/or trituration and/or
preparative HPLC.
General Procedure 5 (GP 5): Urea Formation (Conditions A)
[0344] The respective (hetero)aryl amine (1 eq.) was dissolved in
DCM (5-10 mL per mmol amine) and treated with the respective
(commercially available) isocyanate (1-1.2 eq.). The reaction
mixture was stirred at room temperature until TLC indicated
complete consumption of the starting aniline (usually overnight).
The reaction mixture was concentrated in vacuo, the residue was
taken up in ethyl acetate and water was added, the layers were
separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were dried and concentrated in vacuo.
The residue was optionally purified by flash column chromatography
and/or trituration and/or preparative HPLC.
General Procedure 6 (GP 6): Urea Formation (Conditions B)
[0345] 1.2 Eq. of a (hetero)aryl amine (usually the less
functionalized one of the two amines to be coupled) were dissolved
in acetonitrile (.about.8 mL per mmol. amine), treated with
triphosgene (0.4 eq.) and stirred at room temperature for 1 h upon
which the second (hetero)aryl amine (usually the higher
functionalized of the two amines to be coupled) was added and
stirring was continued at r.t. until TLC indicated complete
conversion. The reaction mixture was concentrated in vacuo, the
residue was taken up in ethyl acetate and water was added, the
layers were separated and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were dried and
concentrated in vacuo. The residue was optionally purified by flash
column chromatography and/or trituration and/or preparative
HPLC.
General Procedure 7 (GP 7): N1-Alkylation of
1H-pyrazolopyridines
[0346] The respective 1H-pyrazolopyridine was dissolved in dry DMF
under an atmosphere of argon and treated with sodium hydride and
subsequently stirred at 50.degree. C. for 1 h. A solution of the
respective alkyl halide in DMF was added dropwise and stirring was
continued at 50.degree. C. for 1 h. [In cases were the respective
halide is only available as a salt (e.g. hydrochloride or
hydrobromide salt), this salt was dissolved in DMF and treated with
excess Et.sub.3N, and the resulting slurry was added to the
deprotonated 1H-pyrazolopyridine upon filtration through a
Millipore filter.] The reaction mixture was diluted with EtOAc,
quenched with water, the aqueous layer was extracted with EtOAc and
the combined organic layers were dried and concentrated in vacuo.
Flash column chromatography optionally followed by
recrystallization or preparative HPLC purification yielded the
desired alkylated pyrazolopyridines.
General Procedure 8 (GP 8): Urea Formation with
Phenylcarbamates
[0347] The respective (hetero)aryl amine (1 eq.) was dissolved in
THF (.about.10 mL per mmol amine) and treated with pyridine (40
eq.) and the respective (hetero)aryl carbamic acid phenyl ester (1
eq.; prepared from the respective (hetero)aryl amine precursor by
treatment with phenyl chloroformate in analogy to procedures
described in WO2007064872 or WO2005110994)). The reaction mixture
was heated to 100.degree. C. for 15 min in a Biotage Initiator
microwave oven upon which LCMS analysis usually showed complete
turnover (otherwise heating to 100.degree. C. was continued until
LCMS analysis showed completion of turnover). The reaction mixture
was concentrated in vacuo and the residue was isolated either by
trituration or by flash column chromatography or by preparative
HPLC purification.
General Procedure 9 (GP 9): Formation of Isopropenyl Carbamates
[0348] In analogy to J. Org. Chem. 2005, 70, 6960
[0349] The respective (hetero)aryl amine (1 eq.) was dissolved in
THF (.about.2.5 mL per mmol amine) and treated with
N-methylmorpholine (1.2 eq.). The resulting solution was cooled to
4.degree. C. and treated dropwise with chloro-isopropenyl formate
(1.2 eq.). Stirring was continued at rt until TLC or LCMS analysis
showed completion of turnover. The reaction mixture was quenched
with water and usually extracted with ethyl acetate. The combined
organic layers were dried and concentrated in vacuo. Trituration of
the residue provided the target carbamate.
General Procedure 10 (GP 10): Urea Formation with Isopropenyl
Carbamates
[0350] In analogy to J. Org. Chem. 2005, 70, 6960
[0351] The respective (hetero)aryl amine (1 eq.) was dissolved in
THF (.about.4 mL per mmol amine) and treated with
N-methylpyrrolidine (0.2 eq.) and the respective (hetero)aryl
carbamic acid isopropenyl ester (1-1.5 eq.). The mixture was
stirred overnight at 55.degree. C. Extractive work-up followed by
trituration and/or flash column chromatograpy and/or preparative
HPLC purification provided the target urea.
Synthesis of Key Intermediates
Intermediate 1.1
Preparation of
N-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-N'-methyl-hydrazine
##STR00018##
[0353] In analogy to GP 1, 2.15 g of
3,5-dibromo-pyridine-4-carbaldehyde (8.12 mmol, 1 eq; commercially
available or prepared as described in U.S. Pat. No. 6,232,320 or
WO2005110410) were dissolved in 36 mL 1-PrOH, treated with 0.65 mL
N-methyl hydrazine (12.17 mmol, 1.5 eq.) and heated to 100.degree.
C. for 30 min (employing a Biotage Initiator.RTM. microwave oven in
batch mode). The reaction mixture was concentrated, the residue
partitioned between water and ethyl acetate, the aqueous layer
reextracted with ethyl acetate, the combined organic layers dried
and concentrated in vacuo to yield 2.29 g of the desired product
(7.82 mmol, 96% yield), which was used in the subsequent
cyclization without further purification steps.
[0354] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 8.57-8.63 (m, 3H); 7.22
(s, 1H); 2.86 (d, 3H).
[0355] .sup.13C-NMR (d.sub.6-DMSO; 150 MHz): 151.27 (CH); 141.44
(C.sub.q); 124.39 (CH); 119.34 (C.sub.q); 32.83 (CH.sub.3).
[0356] MS (ESI): [M+H].sup.+=294 (Br.sub.2 isotope pattern)
Intermediate 1.2
Preparation of
2-{N'-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazino}-ethanol
##STR00019##
[0358] In analogy to GP1, 468 mg of
3,5-dibromo-pyridine-4-carbaldehyde (1.77 mmol, 1 eq; commercially
available or prepared as described in U.S. Pat. No. 6,232,320 or
WO2005110410) were dissolved in 8 mL 1-PrOH, treated with 0.36 mL
2-hydrazino-ethanol (5.3 mmol, 3 eq.) and heated to 120.degree. C.
for 30 min (employing a Biotage Initiator.RTM. microwave oven). The
reaction mixture was concentrated, the residue partitioned between
water and ethyl acetate, the aqueous layer reextracted with ethyl
acetate, the combined organic layers dried and concentrated in
vacuo to yield 530 mg of the desired product (1.64 mmol, 93%
yield), which was used in the subsequent cyclization without
further purification steps.
[0359] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 8.59 (s, 2H); 8.55 (t,
1H); 7.51 (s, 1H); 4.70 (t, 1H); 3.58 (q, 2H); 3.25 (q, 2H).
[0360] MS (ESI): [M+H].sup.+=324 (Br.sub.2 isotope pattern)
Intermediate 1.3
Preparation of
[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazine
##STR00020##
[0362] In analogy to GP 1, 54 mg of
3,5-dibromo-pyridine-4-carbaldehyde (0.2 mmol, 1 eq; commercially
available or prepared as described in U.S. Pat. No. 6,232,320 or
WO2005110410) were dissolved in 1 mL 1-PrOH, treated with 30 .mu.L
80% hydrazine hydrate (0.61 mmol, 3 eq.) and heated to 120.degree.
C. for 30 min (employing a Biotage Initiator.RTM. microwave oven).
The precipitate was filtered and washed with cold 1-PrOH to yield
27 mg of the hydrazone (0.1 mmol, 50% yield).
[0363] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 8.61 (s, 2H); 7.96 (s,
2H); 7.72 (s, 1H).
[0364] MS (LC-MS): >90% pure; [M+H].sup.+=279 (Br.sub.2 isotope
pattern)
Intermediate 1.4
Preparation of
N'-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazinecarboxylic
acid tert-butyl ester
##STR00021##
[0366] In analogy to GP 1, 1.37 g of
3,5-dibromo-pyridine-4-carbaldehyde (5.17 mmol, 1 eq; commercially
available or prepared as described in U.S. Pat. No. 6,232,320 or
WO2005110410) were dissolved in 24 mL 1-PrOH, treated with 2.05 g
tert-butyl carbazate (15.5 mmol, 3 eq.) and heated to 120.degree.
C. for 30 min (employing a Biotage Initiator.RTM. microwave oven in
batch mode). The precipitate was filtered and washed with cold
1-PrOH to yield 1.66 g of the Boc-hydrazone (4.37 mmol, 85%
yield).
[0367] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 11.36 (br., 1H); 8.74
(s, 2H); 8.04 (s, 1H); 1.44 (s, 9H).
Intermediate 1.5
Preparation of
N-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-N'-ethyl-hydrazine
##STR00022##
[0369] In analogy to GP 1, 2.65 g of
3,5-dibromo-pyridine-4-carbaldehyde (10 mmol, 1 eq; commercially
available or prepared as described in U.S. Pat. No. 6,232,320 or
WO2005110410) were dissolved in 32 mL 1-PrOH, treated with 2.25 g
N-ethyl hydrazine (oxalate salt; 15 mmol, 1.5 eq.) and heated to
100.degree. C. for 30 min (employing a Biotage Initiator.RTM.
microwave oven in batch mode). The reaction mixture was
concentrated, the residue partitioned between conc. aq. NaHCO.sub.3
solution and ethyl acetate, the aqueous layer reextracted with
ethyl acetate, the combined organic layers dried and concentrated
in vacuo to yield 3.08 g of the desired product (10 mmol,
quantitative yield), which was used in the subsequent cyclization
without further purification steps.
[0370] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 8.60 (s, 2H); 8.53 (t,
1H); 7.40 (s, 1H); 3.18 (dq, 2H); 1.16 (t, 3H).
Intermediate 2.1
Preparation of 4-Bromo-1-methyl-1H-pyrazolo[3,4-c]pyridine
##STR00023##
[0372] In analogy to GP 2, 5.34 g of
N-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-N'-methyl-hydrazine
(Intermediate 1.1, 18.23 mmol, 1 eq) were dissolved in 163 mL dry
THF, treated at rt with 994 mg 50-60% NaH (22.78 mmol, 1.2 eq) and
subsequently refluxed for 90 min. The reaction mixture was quenched
with water, extracted with ethyl acetate, the combined organic
layers dried and concentrated in vacuo. The precipitate was
filtered and subsequently triturated with diisopropylether to yield
1.71 g of the desired product. Flash column chromatography of the
mother liquor provided a second batch of the analytically pure
product.
[0373] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.16 (s, 1H); 8.34 (s,
1H); 8.16 (s, 1H); 4.17 (s, 3H).
[0374] MS (ESI): [M+H].sup.+=212 (Br isotope pattern).
Intermediate 2.2
Preparation of 2-(4-Bromo-pyrazolo[3,4-c]pyridin-1-yl)-ethanol
##STR00024##
[0376] In analogy to GP2, 520 mg of
2-{N'-[1-(3,5-Dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazino}-ethanol
(Intermediate 1.2, 1.61 mmol, 1 eq) were dissolved in 14 mL dry
THF, treated at rt with 155 mg 50-60% NaH (3.54 mmol, 2.2 eq) and
subsequently refluxed for 90 min. The reaction mixture was quenched
with water, extracted with ethyl acetate, the combined organic
layers dried and concentrated in vacuo to yield 424 mg of a crude
product, which was optionally further purified by trituration or
flash column chromatography.
[0377] LC-MS: [M+H].sup.+=243 (Br isotope pattern)
Intermediate 2.3
Preparation of 4-Bromo-1H-pyrazolo[3,4-c]pyridine
##STR00025##
[0379] In analogy to GP 2, 578 mg of
[1-(3,5-dibromo-pyridin-4-yl)-meth-(E)-ylidene]-hydrazine
(Intermediate 1.3, 2.07 mmol, 1 eq) were dissolved in 18 mL dry
THF, treated at rt with 200 mg 50-60% NaH (4.56 mmol, 2.2 eq) and
subsequently refluxed for 90 min. The reaction mixture was quenched
with water, extracted with ethyl acetate, the combined organic
layers dried and concentrated in vacuo.
[0380] MS (LC-MS): [M+H].sup.+=198 (Br.sub.2 isotope pattern)
Intermediate 2.4
Preparation of 4-Bromo-1-ethyl-1H-pyrazolo[3,4-c]pyridine
##STR00026##
[0382] In analogy to GP 2, 2.1 g of Intermediate 1.5 (6.83 mmol, 1
eq) were dissolved in 60 mL dry THF, treated at rt with 372 mg
50-60% NaH (8.53 mmol, 1.25 eq) and subsequently refluxed for 90
min. The reaction mixture was quenched with water, extracted with
ethyl acetate, the combined organic layers dried and concentrated
in vacuo. The precipitate was filtered and subsequently triturated
with diisopropylether to yield 1.6 g of the desired product
(quantitative yield).
[0383] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.20 (s, 1H); 8.34 (s,
1H); 8.18 (s, 1H); 4.56 (q, 2H); 1.42 (t, 3H).
Intermediate 2.5
Preparation of
4-Bromo-1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridine
##STR00027##
[0385] A solution of 675 mg of
2-(4-bromo-pyrazolo[3,4-c]pyridin-1-yl)-ethanol (Intermediate 2.2;
2.79 mmol, 1 eq.) in 33 mL THF was treated at Rt with 183 mg NaH
(55-60% suspension; 4.18 mmol, 1.5 eq.) and stirred for 30 min upon
which 0.194 mL methyl iodide (3.07 mmol, 1.1 eq.) were added and
stirring was continued for 2 h. The reaction mixture was quenched
with water, extracted with ethyl acetate, the combined organic
layers were dried and concentrated in vacuo. Flash column
chromatography provided 500 mg of the corresponding methyl ether
target compound (1.95 mmol, 70% yield).
Intermediate 2.6
Preparation of
4-Bromo-1-(2-bromo-ethyl)-1H-pyrazolo[3,4-c]pyridine
##STR00028##
[0387] A solution of 709 mg of
2-(4-bromo-pyrazolo[3,4-c]pyridin-1-yl)-ethanol (Intermediate 2.2;
2.93 mmol, 1 eq.) in 3 mL DMF was treated at Rt with 1.93 g
Ph.sub.3P (7.32 mmol, 2.5 eq.) and 1.94 g CBr.sub.4 (5.86 mmol, 2
eq.) and stirred for 90 min at rt. The reaction mixture was
quenched with water, extracted with DCM, the combined organic
layers were dried and concentrated in vacuo. Flash column
chromatography provided 290 mg of the bromo compound (0.95 mmol,
33% yield).
[0388] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.25 (s, 1H); 8.37 (s,
1H); 8.27 (d, 1H); 4.98 (t, 2H); 3.96 (t, 2H).
Intermediate 2.7
Preparation of
4-Bromo-1-(2-methanesulfonyl-ethyl)-1H-pyrazolo[3,4-c]pyridine
##STR00029##
[0390] 100 mg of
4-Bromo-1-(2-bromo-ethyl)-1H-pyrazolo[3,4-c]pyridine (Intermediate
2.6; 0.33 mmol, 1 eq.) were dissolved in 5 mL EtOH and treated with
150 mg sodium methyl sulfinate (1.5 mmol, 4.5 eq.) and heated to
120.degree. C. for 4 h in a Biotage Initiator microwave oven. The
reaction mixture was quenched with water, extracted with DCM, the
combined organic layers were dried and concentrated in vacuo to
provide the crude Intermediate 2.7, which was used without further
purification in the subsequent transformations.
[0391] MS (LC-MS): [M+H].sup.+=304/306 (Br isotope pattern)
Intermediate 3.1
Preparation of
4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
##STR00030##
[0393] In analogy to GP 3, 1.06 g of Intermediate 2.1 (5 mmol, 1
eq.), 1.31 g of
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (6
mmol, 1.2 eq.) and 347 mg Pd(PPh.sub.3).sub.4 (6 mol %) were
weighed into a Biotage microwave vial and capped. 30 mL toluene, 30
mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (9.65 mL, 1.9 eq.)
were subsequently added by syringe. The resulting mixture was
prestirred (10 sec) and subsequently heated to 120.degree. C. for
15 min (fixed hold time) in a Biotage Initiator.RTM. microwave
reactor. The reaction mixture was diluted with water and ethyl
acetate, the layers were separated and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried and
concentrated in vacuo to yield after trituration 701 mg of the
desired product (3.13 mmol, 63% yield), which was used for
subsequent transformations without further purification.
[0394] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 8.97 (s, 1H); 8.24-8.25
(m, 2H); 7.46 (d, 2H); 6.69 (d, 2H); 5.40 (br. s, 2H); 4.15 (s,
3H).
Intermediate 3.2
Preparation of
2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
##STR00031##
[0396] In analogy to GP 3, 390 mg of Intermediate 2.1 (1.84 mmol, 1
eq.), 523.24 mg of
2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine
(2.21 mmol, 1.2 eq.) and 127.5 mg Pd(PPh.sub.3).sub.4 (0.11 mmol, 6
mol %) were weighed into a Biotage microwave vial and capped. 7.5
mL toluene, 7.5 mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (3.55
mL, 1.9 eq.) were subsequently added by syringe. The resulting
mixture was prestirred (10 sec) and subsequently heated to
120.degree. C. for 15 min (fixed hold time) in a Biotage
Initiator.RTM. microwave reactor. The reaction mixture was diluted
with water and ethyl acetate, the layers were separated and the
aqueous layer extracted with ethyl acetate. The combined organic
layers were dried and concentrated in vacuo to yield after
trituration 294 mg of the desired product (1.21 mmol, 66% yield),
which was used for subsequent transformations without further
purification.
[0397] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.01 (s, 1H); 8.28-8.30
(m, 2H); 7.42 (dd, 1H); 7.35 (dd, 1H); 6.89 (dd, 1H); 5.45 (br. s,
2H); 4.16 (s, 3H).
[0398] MS (ESI): [M+H].sup.+=243.
Intermediate 3.3
Preparation of
2-Methyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
##STR00032##
[0400] In analogy to GP 3, 228 mg of Intermediate 2.1 (1.08 mmol, 1
eq.), 455.7 mg of
2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine
(1.29 mmol, 1.2 eq.) and 74.6 mg Pd(PPh.sub.3).sub.4 (0.065 mmol, 6
mol %) were weighed into a Biotage microwave vial and capped. 8 mL
toluene, 8 mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (2.08 mL,
1.9 eq.) were subsequently added by syringe. The resulting mixture
was prestirred (10 sec) and subsequently heated to 120.degree. C.
for 15 min (fixed hold time) in a Biotage Initiator.RTM. microwave
reactor. The reaction mixture was diluted with water and ethyl
acetate, the layers were separated and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried and
concentrated in vacuo to yield after flash column chromatography 89
mg of the desired product (0.37 mmol, 35% yield).
[0401] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 8.96 (s, 1H); 8.24-8.25
(m, 2H); 7.32-7.37 (m, 2H); 6.73 (d, 1H); 5.14 (br. s, 2H); 4.15
(s, 3H); 2.12 (s, 3H).
[0402] MS (ESI): [M+H].sup.+=239.
Intermediate 3.4
Preparation of
2-Methoxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
##STR00033##
[0404] In analogy to GP 4, 355 mg of Intermediate 2.1 (1.67 mmol, 1
eq.), 630 mg of
2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phen-
ylamine (2.51 mmol, 1.5 eq.) and 268 mg of FibreCat 1032 (0.1 mmol,
6 mol %) were weighed into a Biotage microwave vial and capped. 15
mL EtOH and 2.51 mL 1M aq. K.sub.2CO.sub.3 solution (2.51 mmol, 1.5
eq.) were added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 130.degree. C. for 20 min in a
Biotage Initiator.RTM. microwave oven. After filtration and
concentration in vacuo, the residue was taken up in ethyl acetate
and water was added, the layers were separated and the aqueous
layer was extracted with ethyl acetate. The combined organic layers
were dried and concentrated in vacuo. Flash column chromatography
yielded 231 mg of the desired product (0.90 mmol, 54% yield) along
with additional fractions of impure material.
[0405] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 8.99 (s, 1H); 8.30-8.32
(m, 2H); 7.12-7.16 (m, 2H); 6.76 (d, 1H); 5.03 (br. s, 2H); 4.16
(s, 3H); 3.85 (s, 3H).
[0406] MS (ESI): [M+H].sup.+=255.
Intermediate 3.5
Preparation of
4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
##STR00034##
[0408] In analogy to GP 3, 1.65 g of Intermediate 2.4 (7.3 mmol, 1
eq.), 2.88 g of
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (13.1
mmol, 1.8 eq.) and 506 mg Pd(PPh.sub.3).sub.4 (6 mol %) were
weighed into Biotage microwave vials and capped. 15 mL toluene, 15
mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (14 mL, 1.9 eq.) were
subsequently added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 120.degree. C. for 15 min
(fixed hold time) in a Biotage Initiator.RTM. microwave reactor
(reaction was run in two batches). The combined reaction mixtures
were diluted with water and ethyl acetate, the layers were
separated and the aqueous layer extracted with ethyl acetate. The
combined organic layers were dried and concentrated in vacuo to
yield after flash column chromatography 1200 mg of the desired
product (5.04 mmol, 69% yield).
[0409] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.01 (s, 1H); 8.25 (s,
1H); 8.24 (s, 1H); 7.46 (d, 2H); 6.69 (d, 2H); 5.39 (br. s, 2H);
4.55 (q, 2H); 1.42 (t, 3H).
[0410] MS (ESI): [M+H].sup.+=239.
Intermediate 3.6
Preparation of
4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenylamine
##STR00035##
[0412] In analogy to GP 3, 825 mg of Intermediate 2.4 (3.65 mmol, 1
eq.), 1.0 g of
2-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl-
amine (4.2 mmol, 1.15 eq.) and 253 mg Pd(PPh.sub.3).sub.4 (6 mol %)
were weighed into a Biotage microwave vial and capped. 6.5 mL
toluene, 6.5 mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (7 mL,
1.9 eq.) were subsequently added by syringe. The resulting mixture
was prestirred (10 sec) and subsequently heated to 120.degree. C.
for 15 min (fixed hold time) in a Biotage Initiator.RTM. microwave
reactor. The reaction mixture was diluted with water and ethyl
acetate, the layers were separated and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried and
concentrated in vacuo to yield after flash column chromatography
903 mg of the desired product.
[0413] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.05 (s, 1H); 8.29 (s,
1H); 8.28 (s, 1H); 7.42 (dd, 1H); 7.34 (dd, 1H); 6.89 (dd, 1H);
5.44 (s, 2H); 4.56 (q, 2H); 1.42 (t, 3H).
[0414] MS (ESI): [M+H].sup.+=257.
Intermediate 3.7
Preparation of
4-[1-(2-Methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenylamine
##STR00036##
[0416] In analogy to GP 3, 300 mg of
4-bromo-1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridine
(Intermediate 2.5; 1.17 mmol, 1 eq.), 462 mg of
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (2.11
mmol, 1.8 eq.) and 81.22 mg Pd(PPh.sub.3).sub.4 (6 mol %) were
weighed into a Biotage microwave vial and capped. 2.1 mL toluene,
2.1 mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (2.25 mL, 1.9 eq.)
were subsequently added by syringe. The resulting mixture was
prestirred (10 sec) and subsequently heated to 120.degree. C. for
15 min (fixed hold time) in a Biotage Initiator.RTM. microwave
reactor. The reaction mixture was diluted with water and ethyl
acetate, the layers were separated and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried and
concentrated in vacuo to yield after flash column chromatography
148 mg of the desired product (0.55 mmol, 47% yield) along with a
second slightly impure batch of 140 mg.
[0417] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 8.98 (s, 1H); 8.26 (s,
1H); 8.22 (s, 1H); 7.46 (d, 2H); 6.70 (d, 2H); 5.38 (br. s, 2H);
4.69 (t, 2H); 3.76 (t, 2H); 3.17 (s, 3H).
Intermediate 3.8
Preparation of
2-fluoro-4-[1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenylami-
ne
##STR00037##
[0419] In analogy to GP 3, 200 mg of
4-bromo-1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridine
(Intermediate 2.5; 0.78 mmol, 1 eq.), 333 mg of
2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine
(1.41 mmol, 1.8 eq.) and 54 mg Pd(PPh.sub.3).sub.4 (6 mol %) were
weighed into a Biotage microwave vial and capped. 1.4 mL toluene,
1.4 mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (1.5 mL, 1.9 eq.)
were subsequently added by syringe. The resulting mixture was
prestirred (10 sec) and subsequently heated to 120.degree. C. for
15 min (fixed hold time) in a Biotage Initiator.RTM. microwave
reactor. The reaction mixture was diluted with water and ethyl
acetate, the layers were separated and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried and
concentrated in vacuo to yield after flash column chromatography
the desired product (80% yield).
[0420] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.02 (s, 1H); 8.31 (s,
1H); 8.26 (s, 1H); 7.42 (dd, 1H); 7.34 (dd, 1H); 6.89 (dd, 1H);
5.44 (s, 2H); 4.69 (t, 2H); 3.76 (t, 2H); 3.17 (s, 3H).
Intermediate 4.1
Preparation of
[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-carbamic acid
isopropenyl ester
##STR00038##
[0422] In analogy to J. Org. Chem. 2005, 70, 6960 and GP 9:
[0423] 950 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1, 4.24 mmol, 1 eq.) were dissolved in 10 mL THF
and treated with 0.56 mL N-methylmorpholine (5.08 mmol, 1.2 eq.).
The resulting solution was cooled to 4.degree. C. and treated
dropwise with 0.55 mL chloro-isopropenyl formate (5.08 mmol, 1.2
eq.). Stirring was continued at rt for 4 h. The reaction mixture
was quenched with water and extracted with ethyl acetate. The
combined organic layers were dried and concentrated in vacuo.
Trituration of the residue provided 674 mg of the target carbamate
(2.2 mmol, 52% yield).
[0424] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 10.11 (br. s, 1H); 9.09
(s, 1H); 8.35 (s, 1H); 8.31 (s, 1H); 7.74 (d, 2H); 7.63 (d, 2H);
4.73-4.75 (m, 2H); 4.18 (s, 3H); 1.93 (s, 3H).
Intermediate 4.2
Preparation of
[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-carbamic
acid isopropenyl ester
##STR00039##
[0426] In analogy to J. Org. Chem. 2005, 70, 6960 and GP 9:
[0427] 485 mg of
2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.2, 2 mmol, 1 eq.) were dissolved in 7 mL THF and
treated with 0.26 mL N-methylmorpholine (2.4 mmol, 1.2 eq.). The
resulting solution was cooled to 4.degree. C. and treated dropwise
with 0.26 mL chloro-isopropenyl formate (2.4 mmol, 1.2 eq.).
Stirring was continued at rt for 4 h. The reaction mixture was
quenched with water and extracted with ethyl acetate. The combined
organic layers were dried and concentrated in vacuo. Trituration of
the residue provided 109 mg of the target carbamate (0.33 mmol, 17%
yield).
[0428] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.81 (br. s, 1H); 9.14
(s, 1H); 8.40 (s, 1H); 8.35 (s, 1H); 7.82 (t, 1H); 7.60-7.70 (m,
2H); 4.72-4.75 (m, 2H); 4.20 (s, 3H); 1.93 (s, 3H).
Intermediate 5.1
Preparation of
[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-carbamic
acid phenyl ester
##STR00040##
[0430] 484 mg of
2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.2; 2 mmol, 1 eq.) were dissolved in 35 mL THF and
0.21 mg Na.sub.2CO.sub.3 (2 mmol, 1 eq.) were added. 0.76 mL of
phenyl chloro formate (6 mmol, 3 eq.) were added dropwise and
stirring was continued at rt overnight. The reaction mixture was
quenched with water, extracted with ethyl acetate, the combined
organic layers were dried and concentrated in vacuo. Flash column
chromatography provided 415 mg (57% yield) of the target
compound.
[0431] MS (LC-MS): [M+H].sup.+=363.
Synthesis of Example Compounds
Example Compound 1.1
Preparation of
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-phenyl-urea
##STR00041##
[0433] In analogy to GP 5, 112 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.5 mmol, 1 eq.) were dissolved in 5.2 mL DCM
and treated with 60 .mu.L phenyl isocyanate (0.55 mmol, 1.1 eq.).
Work-up as described in GP 5 and flash column chromatography
followed by trituration provided 29 mg of the analytically pure
product (0.084 mmol, 17% yield).
[0434] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.08 (s, 1H); 8.87 (s,
1H); 8.71 (s, 1H); 8.35 (s, 1H); 8.31 (d, 1H); 7.72 (d, 2H); 7.62
(d, 2H); 7.45 (dd, 2H); 7.26 (t, 2H); 6.95 (tt, 1H); 4.18 (s,
3H).
[0435] MS (ESI): [M+H].sup.+=344.
Example Compound 1.2
Preparation of
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea
##STR00042##
[0437] In analogy to GP 5, 112 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.5 mmol, 1 eq.) were dissolved in 5.2 mL DCM
and treated with 80 .mu.L
1-fluoro-2-isocyanato-4-trifluoromethyl-benzene (0.55 mmol, 1.1
eq.). Work-up as described in GP 5 and flash column chromatography
followed by trituration provided 27 mg of the analytically pure
product (0.063 mmol, 13% yield).
[0438] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.40 (s, 1H); 9.10 (s,
1H); 8.96 (s, 1H); 8.61 (dd, 1H); 8.36 (s, 1H); 8.31 (s, 1H); 7.75
(d, 2H); 7.64 (d, 2H); 7.48 (dd, 1H); 7.35-7.39 (m, 1H); 4.19 (s,
3H).
[0439] MS (ESI): [M+H].sup.+=430.
Example Compound 1.3
Preparation of
1-(2-Fluoro-5-methyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-y-
l)-phenyl]-urea
##STR00043##
[0441] In analogy to GP 5, 112 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.5 mmol, 1 eq.) were dissolved in 5.2 mL DCM
and treated with 72 .mu.L 1-fluoro-2-isocyanato-4-methyl-benzene
(0.55 mmol, 1.1 eq.). Work-up as described in GP 5 and flash column
chromatography followed by trituration provided 30 mg of the
analytically pure product (0.080 mmol, 16% yield).
[0442] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.25 (s, 1H); 9.09 (s,
1H); 8.51 (d, 1H); 8.36 (s, 1H); 8.31 (s, 1H); 7.97 (dd, 1H); 7.73
(d, 2H); 7.62 (d, 2H); 7.08 (dd, 2H); 6.76-6.80 (m, 1H); 4.19 (s,
3H); 2.25 (s, 3H).
[0443] MS (ESI): [M+H].sup.+=376.
Example Compound 1.4
Preparation of
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trifluorometh-
yl-phenyl)-urea
##STR00044##
[0445] In analogy to GP 5, 112 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.5 mmol, 1 eq.) were dissolved in 5.2 mL DCM
and treated with 77 .mu.L 1-isocyanato-3-trifluoromethyl-benzene
(0.55 mmol, 1.1 eq.). Work-up as described in GP 5 followed by
trituration provided 59 mg of the analytically pure product (0.143
mmol, 29% yield).
[0446] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.10 (s, 1H); 9.09 (s,
1H); 9.02 (s, 1H); 8.36 (s, 1H); 8.31 (s, 1H); 8.01 (s, 1H); 7.74
(d, 2H); 7.64 (d, 2H); 7.58 (d, 1H); 7.50 (t, 1H); 7.29 (d, 1H);
4.19 (s, 3H).
[0447] MS (ESI): [M+H].sup.+=412.
Example Compound 1.5
Preparation of
1-(3-Ethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-
-urea
##STR00045##
[0449] In analogy to GP 5, 224 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 1 mmol, 1 eq.) were dissolved in 10 mL DCM and
treated with 160 .mu.L 1-ethyl-3-isocyanato-benzene (1.1 mmol, 1.1
eq.). Work-up as described in GP 5 followed by flash column
chromatography and trituration provided 120 mg of the analytically
pure product (0.323 mmol, 32% yield).
[0450] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.08 (s, 1H); 8.84 (s,
1H); 8.64 (s, 1H); 8.35 (s, 1H); 8.31 (s, 1H); 7.72 (d, 2H); 7.62
(d, 2H); 7.31 (s, 1H); 7.25 (d, 1H); 7.16 (t, 1H); 6.80 (d, 1H);
4.18 (s, 3H); 2.55 (q, 2H); 1.15 (t, 3H).
[0451] MS (ESI): [M+H].sup.+=372.
Example Compound 1.6
Preparation of
1-(3-Ethoxy-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl-
]-urea
##STR00046##
[0453] In analogy to GP 5, 224 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 1 mmol, 1 eq.) were dissolved in 10 mL DCM and
treated with 150 .mu.L 1-ethoxy-3-isocyanato-benzene (1.1 mmol, 1.1
eq.). Work-up as described in GP 5 followed by flash column
chromatography and trituration provided 93 mg of the analytically
pure product (0.24 mmol, 24% yield).
[0454] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.09 (s, 1H); 8.87 (s,
1H); 8.71 (s, 1H); 8.35 (s, 1H); 8.31 (s, 1H); 7.72 (d, 2H); 7.62
(d, 2H); 7.12-7.17 (m, 2H); 6.90 (dd, 1H); 6.51 (dd, 1H); 4.18 (s,
3H); 3.97 (q, 2H); 1.30 (t, 3H).
[0455] MS (ESI): [M+H].sup.+=388.
Example Compound 1.7
Preparation of
1-(4-Ethyl-pyridin-2-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-p-
henyl]-urea
##STR00047##
[0457] In analogy to GP 10, 112 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.5 mmol, 1 eq.) were dissolved in 2 mL THF and
treated with 10 .mu.L N-methylpyrrolidine (0.1 mmol, 0.2 eq.) and
103 mg (4-ethyl-pyridin-2-yl)-carbamic acid isopropenyl ester
(prepared in analogy to the above cited publication; 0.5 mmol, 1.0
eq.). The mixture was stirred overnight at 55.degree. C. Extractive
work-up followed by trituration and preparative HPLC purification
provided the target compound.
[0458] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 10.83 (s., 1H); 9.44
(s, 1H); 9.10 (s, 1H); 8.36 (s, 1H); 8.31 (s, 1H); 8.16 (d, 1H);
7.75 (d, 2H); 7.69 (d, 2H); 7.31 (d, 1H); 6.88 (dd, 1H); 4.19 (s,
3H); 2.57 (q, 2H); 1.15 (q, 3H).
[0459] MS (ESI): [M+H].sup.+=373.
Example Compound 1.8
Preparation of
1-(4-Ethoxy-pyridin-2-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)--
phenyl]-urea
##STR00048##
[0461] In analogy to GP 10, 224 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 1 mmol, 1 eq.) were dissolved in 7 mL THF and
treated with 21 .mu.L N-methylpyrrolidine (0.2 mmol, 0.2 eq.) and
445 mg (4-ethoxy-pyridin-2-yl)-carbamic acid isopropenyl ester
(prepared in analogy to the above cited publication; 2 mmol, 2.0
eq.). The mixture was stirred overnight at 55.degree. C. Extractive
work-up followed by trituration provided the target compound.
[0462] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 10.88 (br. s., 1H);
9.41 (s, 1H); 9.09 (s, 1H); 8.36 (s, 1H); 8.32 (s, 1H); 8.08 (d,
1H); 7.75 (d, 2H); 7.69 (d, 2H); 6.99 (d, 1H); 6.61 (dd, 1H); 4.19
(s, 3H); 4.06 (q, 2H); 1.32 (q, 3H).
[0463] MS (ESI): [M+H].sup.+=389.
Example Compound 1.9
Preparation of
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-trifluorometh-
yl-pyridin-2-yl)-urea
##STR00049##
[0465] In analogy GP 10, 224 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 1 mmol, 1 eq.) were dissolved in 7 mL THF and
treated with 21 .mu.L N-methylpyrrolidine (0.2 mmol, 0.2 eq.) and
492 mg (4-ethoxy-pyridin-2-yl)-carbamic acid isopropenyl ester
(prepared in analogy to the above cited publication; 2 mmol, 2.0
eq.). The mixture was stirred overnight at 55.degree. C. Extractive
work-up followed by trituration provided the target compound.
[0466] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.83 (br. s., 2H); 9.10
(s, 1H); 8.53 (d, 1H); 8.36 (s, 1H); 8.31 (s, 1H); 8.06 (s, 1H);
7.76 (d, 2H); 7.68 (d, 2H); 7.34 (d, 1H); 4.19 (s, 3H).
[0467] MS (ESI): [M+H].sup.+=413.
[0468] The following example compounds 1.10 to 1.19 were prepared
from Intermediate by reaction with the respective isocyanates
according to GP 5 in analogy to the afore described procedures for
compounds 1.1 to 1.6.
TABLE-US-00002 Example Structure Name Analytical data 1.10
##STR00050##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-methyl-3-trif-
tuoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.13 (s, 1 H);
9.02 (s, 1 H); 9.01(s, 1 H); 8.40 (s, 1 H); 8.35 (s, 1 H);7.97 (d,
1 H); 7.77 (d, 2 H);7.68 (d, 2 H); 7.54 (dd, 1 H);7.36 (d, 1 H);
4.23 (s, 3 H);2.39 (s, 3 H).MS (ESI):[M + H].sup.+ = 426. 1.11
##STR00051##
1-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300MHz)9.26 (s, 1 H);
9.14 (s, 1 H); 9.11(s, 1 H); 8.40 (s, 1 H); 8.35 (s, 1 H);8.14 (d,
1 H); 7.78 (d, 2 H);7.62-7.70 (m, 4 H); 4.23 (s, 3 H).MS (ESI):[M +
H].sup.+ = 446. 1.12 ##STR00052##
1-(2-Chloro-5-methyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-y-
l)-phenyl]-urea .sup.1H-NMR:(DMSO, 400 MHz)9.59 (s, 1 H); 9.09 (s,
1 H); 8.36(s, 1 H); 8.32 (s, 1 H); 8.28 (s, 1 H):8.00 (s, 1 H);
7.74 (d, 2 H);7.64 (d, 2 H); 7.30 (d, 1 H);6.83 (d, 1 H); 4.19 (s,
3 H);2.26 (s, 3 H).MS (ESI):[M + H].sup.+ = 392. 1.13 ##STR00053##
1-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 400 MHz)9.75 (s, 1 H);
9.10 (s, 1 H); 8.65(s, 1 H): 8.63 (d, 1 H); 8.36 (s,1 H); 8.32 (s,
1 H); 7.76 (d, 2 H);7.70 (d, 1 H); 7.65 (d, 2 H);7.36 (dd, 1 H);
4.19 (s, 3 H).MS (ESI):[M + H].sup.+ = 446. 1.14 ##STR00054##
1-(2,3-Dichloro-phenyl)-3-[4-(1-methyl-1H-);pyrazolo[3,4);c]pyridin-4-yl)-
-phenyl]-urea .sup.1H-NMR:(DMSO, 300 MHz)9.68 (s, 1 H); 9.09 (s, 1
H); 8.52(s, 1 H); 8.36 (s, 1 H); 8.31 (s, 1 H);8.16 (dd, 1 H); 7.75
(d, 2 H);7.64 (d, 1 H); 7.32 (d, 1 H);7.26 (dd, 1 H); 4.19 (s, 3
H).MS (MS-ESI):[M + H].sup.+ = 412/414 (Cl.sub.2 isotopepattern).
1.15 ##STR00055##
1-(2-Chloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl-
]-urea MS (MS-ESI):[M + H].sup.+ = 378/380 (Cl isotopepattern).
1.16 ##STR00056##
1-(3-Chloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl-
]- urea MS (MS-ESI):[M + H].sup.+ = 378/380 (Cl isotopepattern).
1.17 ##STR00057##
1-(4-Chloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl-
]-urea MS (MS-ESI):[M + H].sup.+ = 378/380 (Cl isotopepattern).
1.18 ##STR00058##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-trifluorometh-
yl-phenyl)-urea MS (MS-ESI):[M + H].sup.+ = 412. 1.19 ##STR00059##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-m-tolyl-urea
MS (MS-ESI):[M + H].sup.+ = 358.
Example Compound 2.1
Preparation of
1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]p-
yridin-4-yl)-phenyl]-urea
##STR00060##
[0470] In analogy to GP 6, 115 mg of
2-methoxy-5-trifluoromethyl-phenylamine (0.6 mmol, 1.2 eq.) were
dissolved in 10 mL acetonitrile, treated with 59.3 mg triphosgene
(0.2 mmol, 0.4 eq.) and stirred at rt for 1 h upon which a
precipitate was formed. After addition of 112 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.5 mmol, 1 eq.) stirring at rt was continued
for 48 h. Work-up as described in GP 6 followed by trituration and
flash column chromatography provided 19 mg of the analytically pure
product (0.043 mmol, 9% yield).
[0471] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.63 (s, 1H); 9.09 (br.
s, 1H); 8.55 (br. s, 2H); 8.36 (br. s, 1H); 8.31 (s, 1H); 7.74 (d,
2H); 7.64 (d, 2H); 7.30 (d, 1H); 7.18 (d, 1H); 4.19 (s, 3H); 3.95
(s, 3H).
[0472] MS (ESI): [M+H].sup.+=442.
[0473] The following example compounds 2.2 to 2.3 were prepared
from Intermediate 3.1 by triphosgene-mediated coupling with the
respective anilines according to GP 6 in analogy to the afore
described procedures for compounds 2.1. For example compound 2.3,
4-(4-amino-2-trifluoromethyl-benzyl)-piperazine-1-carboxylic acid
tert-butyl ester was used as starting material for the
triphosgene-mediated urea formation. Boc deprotection was achieved
after urea formation by stirring with TFA in DCM.
TABLE-US-00003 Example Structure Name Analytical data 2.2
##STR00061##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-piperidin-1-y-
l-5-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.92
(br. s, 1 H); 9.14 (s, 1 H);8.45 (s, 1 H); 8.41 (s, 1 H);8.36 (s, 1
H); 8.24 (s, 1 H);7.80 (d, 2 H); 7.72 (d, 2 H);7.33 (s, 4 H); 4.23
(s, 3 H);2.83 (t, 4 H); 1.78-1.85(m, 4 H); 1.55-1.63 (m, 2 H).MS
(ESI):[M + H].sup.+ = 495. 2.3 ##STR00062##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-piperazin-1-y-
lmethyl-3-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300
MHz)10.26 (s, 1 H); 10.13 (s, 1 H);9.13 (s, 1 H); 8.45 (s, 1
H);8.40 (s, 1 H); 8.36 (s, 1 H);8.04 (d, 1 H); 7.62-7.78 (m,6 H);
4.24 (s, 3 H); 3.56 (s, 2 H);2.88-2.93 (m, 4 H); 2.42-2.47 (m, 4
H).
Example Compound 3.1
Preparation of
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trif-
luoromethyl-phenyl)-urea
##STR00063##
[0475] In analogy to GP 5, 121 mg of
2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.2; 0.5 mmol, 1 eq.) were dissolved in 5 mL DCM and
treated with 77 .mu.L 1-Isocyanato-3-trifluoromethyl-benzene (0.55
mmol, 1.1 eq.). The reaction mixture was concentrated in vacuo, the
residue was taken up in ethyl acetate, water was added and the
precipitate was filtered, washed with hexane and dried to provide
87 mg of the analytically pure product (0.20 mmol, 41% yield).
[0476] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.45 (s, 1H); 9.13 (s,
1H); 8.82 (d, 1H); 8.40 (s, 1H); 8.36 (s, 1H); 8.31 (t, 1H); 8.03
(s, 1H); 7.70 (dd, 1H); 7.61 (dd, 1H); 7.49-7.55 (m, 2H); 7.32 (d,
1H); 4.19 (s, 3H).
[0477] MS (ESI): [M+H].sup.+=430.
Example Compound 4.1
Preparation of
1-[2-Methyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trif-
luoromethyl-phenyl)-urea
##STR00064##
[0479] In analogy to GP 5, 80 mg of
2-methyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.3; 0.34 mmol, 1 eq.) were dissolved in 3.5 mL DCM
and treated with 52 .mu.L 1-isocyanato-3-trifluoromethyl-benzene
(0.37 mmol, 1.1 eq.). The reaction mixture was concentrated in
vacuo, the residue was taken up in ethyl acetate, water was added
and the precipitate was filtered, washed with hexane and dried to
provide 57 mg of the analytically pure product (0.134 mmol, 39%
yield).
[0480] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.45 (s, 1H); 9.09 (s,
1H); 8.36 (s, 1H); 8.31 (s, 1H); 8.17 (s, 1H); 8.01-8.06 (m, 2H);
7.46-7.64 (m, 4H); 7.29 (d, 1H); 4.19 (s, 3H); 2.34 (s, 3H).
[0481] MS (ESI): [M+H].sup.+=426.
Example Compound 4.2
Preparation of
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[2-methyl-4-(1-methyl-1H-pyrazolo-
[3,4-c]pyridin-4-yl)-phenyl]-urea
##STR00065##
[0483] In analogy to GP 5, 160 mg of
2-methyl-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.3; 0.67 mmol, 1 eq.) were dissolved in 6 mL DCM and
treated with 110 .mu.L
1-fluoro-2-isocyanato-4-trifluoromethyl-benzene (0.74 mmol, 1.1
eq.). The reaction mixture was concentrated in vacuo, the residue
was taken up in ethyl acetate, water was added and the precipitate
was filtered, washed with hexane and dried to provide 75 mg of the
analytically pure product (0.17 mmol, 25% yield).
[0484] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.40 (s, 1H); 9.10 (s,
1H); 8.66 (dd, 1H); 8.61 (s, 1H); 8.36 (s, 1H); 8.31 (s, 1H); 8.08
(d, 1H); 7.63 (s, 1H); 7.60 (dd, 1H); 7.48 (dd, 1H); 7.34-7.38 (m,
1H); 4.19 (s, 3H); 2.35 (s, 3H).
[0485] MS (ESI): [M+H].sup.+=444.
Example Compound 5.1
Preparation of
1-[2-Methoxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-tri-
fluoromethyl-phenyl)-urea
##STR00066##
[0487] In analogy to GP 5, 127 mg of
2-methoxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.4; 0.5 mmol, 1 eq.) were dissolved in 5 mL DCM and
treated with 77 .mu.L 1-isocyanato-3-trifluoromethyl-benzene (0.55
mmol, 1.1 eq.). After work-up as described in GP 5, flash column
chromatography followed by trituration provided 110 mg of the
analytically pure product (0.25 mmol, 50% yield).
[0488] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.77 (s, 1H); 9.15 (s,
1H); 8.49 (s, 1H); 8.46 (s, 1H); 8.42 (s, 1H); 8.35 (d, 1H); 8.07
(s, 1H); 7.52-7.57 (m, 2H); 7.32-7.43 (m, 3H); 4.24 (s, 3H); 4.05
(s, 3H).
[0489] MS (ESI): [M+H].sup.+=442.
Example Compound 5.2
Preparation of
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[2-methoxy-4-(1-methyl-1H-pyrazol-
o[3,4-c]pyridin-4-yl)-phenyl]-urea
##STR00067##
[0491] In analogy to GP 5, 127 mg of
2-methoxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.4; 0.5 mmol, 1 eq.) were dissolved in 5 mL DCM and
treated with 80 .mu.L
1-fluoro-2-isocyanato-4-trifluoromethyl-benzene (0.55 mmol, 1.1
eq.). The reaction mixture was concentrated in vacuo, the residue
was taken up in ethyl acetate, water was added and the precipitate
was filtered, washed with hexane and dried to provide 74 mg of the
analytically pure product (0.16 mmol, 32% yield).
[0492] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.63 (d, 1H); 9.10 (s,
1H); 9.06 (s, 1H); 8.66 (dd, 1H); 8.41 (s, 1H); 8.37 (s, 1H); 8.30
(d, 1H); 7.47 (dd, 1H); 7.33-7.38 (m, 3H); 4.19 (s, 3H); 4.00 (s,
3H);
[0493] MS (ESI): [M+H].sup.+=460.
Example Compound 6.1
Preparation of
1-Methyl-1-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trif-
luoromethyl-phenyl)-urea
##STR00068##
[0495] In analogy to GP 3, 170 mg of Intermediate 2.1 (0.8 mmol, 1
eq.), 403 mg of
1-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-3-(3-trifluoro-methyl-phenyl)-urea (0.96 mmol, 1.2 eq.) and
55.5 mg Pd(PPh.sub.3).sub.4 (0.048 mmol, 6 mol %) were weighed into
a Biotage microwave vial and capped. 8 mL toluene, 8 mL EtOH and 1M
aq. Na.sub.2CO.sub.3 solution (1.54 mL, 1.54 mmol, 1.9 eq.) were
subsequently added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 120.degree. C. for 15 min
(fixed hold time) in a Biotage Initiator.RTM. microwave reactor.
The reaction mixture was diluted with water and ethyl acetate, the
layers were separated and the aqueous layer extracted with ethyl
acetate. The combined organic layers were dried and concentrated in
vacuo to yield after flash column chromatography and trituration 89
mg of the desired product (0.21 mmol, 26% yield).
[0496] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.14 (s, 1H); 8.74 (s,
1H); 8.41 (s, 1H); 8.33 (s, 1H); 7.90 (s, 1H); 7.84 (d, 2H); 7.75
(d, 1H); 7.50 (d, 2H); 7.44 (t, 1H); 7.25 (d, 1H); 4.20 (s, 3H);
3.33 (s, 3H).
[0497] MS (ESI): [M+H].sup.+=426.
Example Compound 6.2
Preparation of
1-Methyl-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-1-(3-trif-
luoromethyl-phenyl)-urea
##STR00069##
[0499] In analogy to GP 3, 170 mg of Intermediate 2.1 (0.8 mmol, 1
eq.), 403 mg of
1-methyl-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-1-(3-trifluoro-methyl-phenyl)-urea (0.96 mmol, 1.2 eq.) and
55.5 mg Pd(PPh.sub.3).sub.4 (0.048 mmol, 6 mol %) were weighed into
a Biotage microwave vial and capped. 8 mL toluene, 8 mL EtOH and 1M
aq. Na.sub.2CO.sub.3 solution (1.54 mL, 1.54 mmol, 1.9 eq.) were
subsequently added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 120.degree. C. for 15 min
(fixed hold time) in a Biotage Initiator.RTM. microwave reactor.
The reaction mixture was diluted with water and ethyl acetate, the
layers were separated and the aqueous layer extracted with ethyl
acetate. The combined organic layers were dried and concentrated in
vacuo to yield after flash column chromatography and trituration 96
mg of the desired product (0.23 mmol, 28% yield).
[0500] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.09 (s, 1H); 8.73 (s,
1H); 8.34 (s, 1H); 8.30 (s, 1H); 7.51-7.71 (m, 8H); 4.18 (s, 3H);
3.35 (s, 3H).
[0501] MS (ESI): [M+H].sup.+=426.
Example Compound 6.3
Preparation of
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-fluo-
ro-5-trifluoromethyl-phenyl)-urea
##STR00070##
[0503] In analogy to GP 3, 106 mg of Intermediate 2.1 (0.5 mmol, 1
eq.), 265 mg of
1-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-3-(2-fluoro-5-tri-fluoromethyl-phenyl)-urea (0.6 mmol, 1.2
eq.) and 35 mg Pd(PPh.sub.3).sub.4 (0.03 mmol, 6 mol %) were
weighed into a Biotage microwave vial and capped. 3 mL toluene, 3
mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (0.96 mL, 0.96 mmol,
1.9 eq.) were subsequently added by syringe. The resulting mixture
was prestirred (10 sec) and subsequently heated to 120.degree. C.
for 15 min (fixed hold time) in a Biotage Initiator.RTM. microwave
reactor. The reaction mixture was diluted with water and ethyl
acetate, the layers were separated and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried and
concentrated in vacuo to yield after trituration 127 mg of the
desired product (0.28 mmol, 57% yield).
[0504] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.42 (s, 1H); 9.33 (s,
1H); 9.13 (s, 1H); 8.63 (dd, 1H); 8.40 (s, 1H); 8.36 (d, 1H); 8.35
(s, 1H); 7.71 (dd, 1H); 7.62 (dd, 1H); 7.49 (dd, 1H); 7.35-7.41 (m,
1H); 4.19 (s, 1H).
[0505] MS (ESI): [M+H].sup.+=448.
Example Compound 6.4
Preparation of
1-[4-(4-Methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(1-me-
thyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
##STR00071##
[0507] In analogy to GP 3, 84.8 mg of Intermediate 2.1 (0.4 mmol, 1
eq.), 249 mg of
1-[4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]--
3-[4-(4,4,5,5-tetra-methyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-urea
(0.48 mmol, 1.2 eq.) and 28 mg Pd(PPh.sub.3).sub.4 (0.024 mmol, 6
mol %) were weighed into a Biotage microwave vial and capped. 2 mL
toluene, 2 mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (0.77 mL,
0.77 mmol, 1.9 eq.) were subsequently added by syringe. The
resulting mixture was prestirred (10 sec) and subsequently heated
to 120.degree. C. for 15 min (fixed hold time) in a Biotage
Initiator.RTM. microwave reactor. The reaction mixture was diluted
with water and ethyl acetate, the layers were separated and the
aqueous layer extracted with ethyl acetate. The combined organic
layers were dried and concentrated in vacuo to yield after
preparative HPLC purification 66.3 mg of the desired product (0.127
mmol, 32% yield).
[0508] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.09 (s, 1H); 9.03 (s,
1H); 8.96 (s, 1H); 8.35 (s, 1H); 8.31 (s, 1H); 7.95 (d, 1H); 7.73
(d, 2H); 7.63 (d, 2H); 7.60 (d, 1H); 7.54-7.57 (m, 1H); 4.19 (s,
3H); 3.50 (s, 2H); 2.21-2.42 (m, 8H); 2.12 (s, 3H).
[0509] MS (ESI): [M+H].sup.+=524.
Example Compound 7.1
Preparation of
1-[2-Hydroxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-tri-
fluoromethyl-phenyl)-urea
##STR00072##
[0511] 157 mg of
1-[2-methoxy-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-tri-
fluoromethyl-phenyl)-urea (Example Compound 5.1; 0.36 mmol, 1 eq.)
were dissolved in 10 mL DCM/DMF (30:1), treated with 0.53 mL
BBr.sub.3 solution (1.0 M in DCM; 0.53 mmol, 1.5 eq) at 0.degree.
C. and subsequently stirred for 1 h at rt. TLC indicated incomplete
conversion. 1.24 mL BBr.sub.3 solution (1.24 mmol, 3.5 eq.) were
added at 0.degree. C. and stirring was continued at rt for 16 h.
The reaction mixture was quenched with aq. NaHCO.sub.3 solution and
diluted with ethyl acetate. The precipitate was filtered off and
the organic layer was dried and concentrated. The residue was
combined with the solid (see above) and triturated from ethyl
acetate to yield 70 mg of the target compound (0.164 mmol, 46%
yield).
[0512] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 10.37 (br., 1H); 9.73
(s, 1H); 9.08 (s, 1H); 8.39 (s, 1H); 8.31 (s, 1H); 8.26 (s, 1H);
8.23 (d, 1H); 8.02 (s, 1H); 7.51 (s, 1H); 7.49 (t, 1H); 7.26-7.29
(m, 2H); 7.21 (dd, 1H); 4.18 (s, 3H).
[0513] MS (ESI): [M+H].sup.+=428.
Example Compound 8.1
Preparation of
1-{2-Fluoro-4-[1-(2-hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea
##STR00073##
[0515] In analogy to GP 3, 80 mg of Intermediate 2.2 (0.33 mmol, 1
eq.), 175 mg of
1-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-ph-
enyl]-3-(2-fluoro-5-tri-fluoromethyl-phenyl)-urea (0.4 mmol, 1.2
eq.) and 23 mg Pd(PPh.sub.3).sub.4 (0.02 mmol, 6 mol %) were
weighed into a Biotage microwave vial and capped. 1.5 mL toluene,
1.5 mL EtOH and 1M aq. Na.sub.2CO.sub.3 solution (0.64 mL, 0.64
mmol, 1.9 eq.) were subsequently added by syringe. The resulting
mixture was prestirred (10 sec) and subsequently heated to
120.degree. C. for 15 min (fixed hold time) in a Biotage
Initiator.RTM. microwave reactor. The reaction mixture was diluted
with water and ethyl acetate, the layers were separated and the
aqueous layer extracted with ethyl acetate. The combined organic
layers were dried and concentrated in vacuo to yield after
trituration 64 mg of the desired product (0.134 mmol, 41%
yield).
[0516] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.43 (s, 1H); 9.33 (s,
1H); 9.13 (s, 1H); 8.64 (dd, 1H); 8.37 (s, 1H); 8.34-8.38 (m, 2H);
7.70 (dd, 1H); 7.62 (dd, 1H); 7.49 (dd, 1H); 7.36-7.41 (m, 1H);
4.90 (t, 1H); 4.60 (t, 2H); 3.82 (q, 2H).
[0517] MS (ESI): [M+H].sup.+=478.
Example Compound 8.2
Preparation of
1-(2-Fluoro-5-trifluoromethyl-phenyl)-3-{4-[1-(2-hydroxy-ethyl)-1H-pyrazo-
lo[3,4-c]pyridin-4-yl]-phenyl}-urea
##STR00074##
[0519] In analogy to GP 3, 230 mg of Intermediate 2.2 (used without
prior purification; 0.95 mmol, 1 eq.), 484 mg of
1-(2-fluoro-5-trifluoromethyl-phenyl)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolan-2-yl)-phenyl]-urea (1.14 mmol, 1.2 eq.) and 66 mg
Pd(PPh.sub.3).sub.4 (0.057 mmol, 6 mol %) were weighed into a
Biotage microwave vial and capped. 4.3 mL toluene, 4.3 mL EtOH and
1M aq. Na.sub.2CO.sub.3 solution (1.83 mL, 1.83 mmol, 1.9 eq.) were
subsequently added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 120.degree. C. for 15 min
(fixed hold time) in a Biotage Initiator.RTM. microwave reactor.
The reaction mixture was diluted with water and ethyl acetate, the
layers were separated and the aqueous layer extracted with ethyl
acetate. The combined organic layers were dried and concentrated in
vacuo to yield after flash column chromatography and trituration 33
mg of the desired product (0.072 mmol, 6% yield).
[0520] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.39 (s, 1H); 9.14 (s,
1H); 8.97 (d, 1H); 8.66 (dd, 1H); 8.38 (s, 1H); 8.37 (s, 1H); 7.79
(d, 2H); 7.69 (d, 2H); 7.53 (dd, 1H); 7.39-7.46 (m, 1H); 4.94 (t,
1H); 4.64 (t, 2H); 3.87 (q, 2H).
[0521] MS (ESI): [M+H].sup.+=460.
Example Compound 8.3
Preparation of
1-{4-[1-(2-Hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3-(3-tr-
ifluoromethyl-phenyl)-urea
##STR00075##
[0523] In analogy to GP 3, 100 mg of Intermediate 2.2 (0.41 mmol, 1
eq.), 201 mg of
1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(-
3-trifluoromethyl-phenyl)-urea (0.5 mmol, 1.2 eq.) and 29 mg
Pd(PPh.sub.3).sub.4 (0.025 mmol, 6 mol %) were weighed into a
Biotage microwave vial and capped. 1.9 mL toluene, 1.9 mL EtOH and
1M aq. Na.sub.2CO.sub.3 solution (0.8 mL, 0.8 mmol, 1.9 eq.) were
subsequently added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 120.degree. C. for 15 min
(fixed hold time) in a Biotage Initiator.RTM. microwave reactor.
The reaction mixture was diluted with water and ethyl acetate, the
layers were separated and the aqueous layer extracted with ethyl
acetate. The combined organic layers were dried and concentrated in
vacuo to yield after flash column chromatography 87 mg of the
desired product (0.197 mmol, 48% yield).
[0524] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.12 (s, 1H); 9.09 (s,
1H); 9.03 (s, 1H); 8.33 (s, 2H); 8.01 (s, 1H); 7.73 (d, 2H); 7.64
(d, 2H); 7.58 (d, 1H); 7.50 (t, 1H); 7.29 (d, 1H); 4.91 (t, 1H);
4.59 (t, 2H); 3.82 (q, 2H).
[0525] MS (ESI): [M+H].sup.+=442.
Example Compound 8.4
Preparation of
1-(3-Ethyl-phenyl)-3-{2-fluoro-4-[1-(2-hydroxy-ethyl)-1H-pyrazolo[3,4-c]p-
yridin-4-yl]-phenyl}-urea
##STR00076##
[0527] In analogy to GP 3, 100 mg of Intermediate 2.2 (0.41 mmol, 1
eq.), 363 mg of
1-(3-ethyl-phenyl)-3-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]di-
oxaborolan-2-yl)-phenyl]-urea (0.95 mmol, 2.3 eq.) and 29 mg
Pd(PPh.sub.3).sub.4 (0.025 mmol, 6 mol %) were weighed into a
Biotage microwave vial and capped. 1.9 mL toluene, 1.9 mL EtOH and
1M aq. Na.sub.2CO.sub.3 solution (0.8 mL, 0.8 mmol, 1.9 eq.) were
subsequently added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 120.degree. C. for 15 min
(fixed hold time) in a Biotage Initiator.RTM. microwave reactor.
The reaction mixture was diluted with water and ethyl acetate, the
layers were separated and the aqueous layer extracted with ethyl
acetate. The combined organic layers were dried and concentrated in
vacuo to yield after flash column chromatography the desired
product.
[0528] MS (ESI): [M+H].sup.+=420.
[0529] The following example compounds 8.5 to 8.6 were prepared
from Intermediate 2.2 by Suzuki coupling according to GP 3 with the
respective boronic acid pinacolate esters in analogy to the afore
described procedures for compounds 8.1 to 8.4.
TABLE-US-00004 Example Structure Name Analytical data 8.5
##STR00077##
1-{2-Fluoro-4-[1-(2-hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(3-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.45
(s, 1 H); 9.12 (s, 1 H);8.80 (s, 1 H); 8.37 (s, 1 H);8.36 (s, 1 H);
8.31 (t, 1 H);8.03 (s, 1 H); 7.69 (dd, 1 H);7.61 (dd, 1H); 7.53 (s,
1 H);7.51 (t, 1 H); 7.32 (d, 1 H);4.91 (t, 1 H); 4.60 (t, 2 H);3.82
(q, 2 H).MS (ESI):[M + H].sup.+ = 460. 8.6 ##STR00078##
1-{4-[1-(2-Hydroxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3-[4-(4-
-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.08 (s, 2 H); 9.00 (s, 1 H);8.32 (s, 2
H); 7.96 (s, 1 H);7.72 (d, 2 H); 7.64 (d, 2 H);7.60 (d, 1 H); 7.56
(dd, 1 H);4.91 (t, 1 H); 4.59 (t, 2 H);3.82 (q, 2 H); 3.50 (s, 2
H);2.23-2.41 (m, 8 H); 2.12 (s,3H).
Example Compound 9.1
Preparation of
1,3-Bis-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yL)-phenyl]-urea
##STR00079##
[0531] Example Compound 9.1 is accessible from Intermediate 3.1 by
triphosgene coupling according to GP 6.
[0532] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.09 (s, 2H); 8.98 (s,
2H); 8.36 (s, 2H); 8.33 (s, 2H); 7.64-7.77 (m, 8H); 4.19 (s,
6H).
[0533] MS (ESI): [M+H].sup.+=475.
Example Compound 10.1
Preparation of
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trifluoromethy-
l-phenyl)-urea
##STR00080##
[0535] In analogy to GP 5, 119 mg of
4-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.5; 0.5 mmol, 1 eq.) were dissolved in 5 mL DCM and
treated with 70 .mu.L 1-isocyanato-3-trifluoromethyl-benzene (0.5
mmol, 1 eq.). The reaction mixture was stirred at rt overnight upon
which it was concentrated in vacuo, the residue was partitioned
between ethyl acetate and water and the aqueous phase was
re-extracted with ethyl acetate several times. The combined organic
layers were dried and concentrated in vacuo. Trituration of the
residue provided 56 mg of the analytically pure target
compound.
[0536] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.13 (s, 1H); 9.09 (s,
1H); 9.00 (s, 1H); 8.35 (s, 1H); 8.32 (s, 1H); 8.01 (s, 1H); 7.73
(d, 2H); 7.64 (d, 2H); 7.58 (d, 1H); 7.49 (t, 1H); 7.29 (d, 1H);
4.59 (q, 2H); 1.44 (t, 3H).
[0537] MS (ESI): [M+H].sup.+=426.
[0538] The following example compounds 10.2 to 10.8 were prepared
from Intermediate by reaction with the respective isocyanates
according to GP 5 in analogy to example compound 10.1.
TABLE-US-00005 Example Structure Name Analytical data 10.2
##STR00081##
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-phenyl-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.12 (s, 1 H); 8.86 (s, 1 H);8.71 (s, 1
H); 8.35 (s, 1 H);8.32 (s, 1 H); 7.72 (d, 2 H);7.62 (d, 2 H); 7.45
(d, 2 H);7.26 (t, 2 H); 6.95 (t, 1 H);4.58 (q, 2 H); 1.44 (t, 3
H).MS (ESI):[M + H].sup.+ = 358. 10.3 ##STR00082##
1-(3-Ethoxy-phenyl)-3-[4-(1-ethyl-1H-pyrazolo[3,4c]pyridin-4-yl)-phenyl]--
urea .sup.1H-NMR:(DMSO, 300 MHz)9.13 (s, 1 H); 8.85 (s, 1 H);8.70
(s, 1 H); 8.34 (s, 1 H);8.32 (s, 1 H); 7.72 (d, 2 H);7.62 (d, 2 H);
7.11-7.18 (m,2 H); 6.90 (dd, 1 H); 6.51 (dd,1 H); 4.58 (q, 2 H);
3.97 (q, 2 H);1.44 (t, 3 H); 1.30 (t, 3 H).MS (ESI):[M + H]+ = 402.
10.4 ##STR00083##
1-[4-(1-Ethyl-1H)-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-fluoro-5-meth-
yl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.24 (s, 1 H); 9.13 (s,
1 H);8.51 (s, 1 H); 8.35 (s, 1 H);8.32 (s, 1 H); 7.98 (dd, 1
H);7.74 (d, 2 H); 7.63 (d, 2 H);7.08 (dd, 1 H); 6.75-6.80 (m,1 H);
4.58 (q, 2 H); 2.25 (s, 3 H);1.44 (t, 3 H).MS (ESI):[M + H]+ = 390.
10.5 ##STR00084##
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]3-(2-fluoro-5-triflu-
oromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.36 (s, 1 H);
9.14 (s, 1 H);8.94 (s, 1 H); 8.61 (dd, 1 H);8.35 (s, 1 H); 8.32 (s,
1 H);7.75 (d, 2 H); 7.64 (d, 2 H);7.49 (dd, 1 H); 7.34-7.40 (m,1
H); 4.58 (q, 2 H); 1.44 (t, 3 H).MS (ESI):[M + H]+ = 444. 10.6
##STR00085##
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-m-tolyl-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.13 (s, 1 H); 8.84 (s, 1 H);8.62 (s, 1
H); 8.34 (s, 1 H);8.32 (s, 1 H); 7.72 (d, 2 H);7.62 (d, 2 H); 7.28
(s, 1 H);7.23 (d, 1 H); 7.14 (t, 1 H);6.77 (d, 1 H); 4.58 (q, 2
H);2.26 (s, 3 H); 1.44 (t, 3 H).MS (ESI):[M + H]+ = 372. 10.7
##STR00086##
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-methoxy-phenyl-
)-urea .sup.1H-NMR:(DMSO, 400 MHz)9.13 (s, 1 H); 8.86 (s, 1 H);8.73
(s, 1 H); 8.34 (s, 1 H);8.32 (s, 1 H); 7.72 (d, 2 H);7.62 (d, 2 H);
7.18 (s, 1 H);7.16 (t, 1 H); 6.92 (d, 1 H);6.53 (d, 1 H); 4.60 (q,
2 H);3.70 (s, 3 H), 1.44 (t, 3 H).MS (ESI):[M + H]+ = 388. 10.8
##STR00087##
1-(3-Ethyl-phenyl)-3-[4-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]--
urea .sup.1H-NMR:(DMSO, 400 MHz)9.13 (s, 1 H); 8.86 (s, 1 H);8.67
(s, 1 H); 8.35 (s, 1 H);8.32 (s, 1 H); 7.72 (d, 2 H);7.62 (d, 2 H);
7.31 (s, 1 H);7.25 (d, 1 H); 7.16 (t, 1 H);6.80 (d, 1 H); 4.59 (q,
2 H);2.55 (q, 2 H); 1.44 (t, 3 H);1.15 (t, 3 H).MS (ESI):[M + H]+ =
386.
Example Compound 11.1
Preparation of
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-(3-trifl-
uoromethyl-phenyl)-urea
##STR00088##
[0540] In analogy to GP 5, 128 mg of
4-(1-ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenylamine
(Intermediate 3.6; 0.5 mmol, 1 eq.) were dissolved in 5 mL DCM and
treated with 70 .mu.L 1-isocyanato-3-trifluoromethyl-benzene (0.5
mmol, 1 eq.). The reaction mixture was stirred at rt overnight upon
which it was concentrated in vacuo, the residue was partitioned
between ethyl acetate and water and the aqueous phase was
re-extracted with ethyl acetate several times. The combined organic
layers were dried and concentrated in vacuo. Trituration of the
residue provided 71 mg of the analytically pure target
compound.
[0541] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.50 (s, 1H); 9.22 (s,
1H); 8.86 (s, 1H); 8.44 (s, 1H); 8.41 (s, 1H); 8.36 (t, 1H); 8.07
(s, 1H); 7.74 (dd, 1H); 7.66 (dd, 1H); 7.53-7.60 (m, 2H); 7.34-7.38
(m, 1H); 4.64 (q, 2H); 1.49 (t, 3H).
[0542] MS (ESI): [M+H].sup.+=444.
[0543] The following example compounds 11.2 to 11.4 were prepared
from Intermediate 3.6 by reaction with the respective isocyanates
according to GP 5 in analogy to example compound 11.1.
TABLE-US-00006 Example Structure Name Analytical data 11.2
##STR00089##
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-(2-fluor-
o-5-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.47
(s, 1 H); 9.37 (s, 1 H);9.22 (s, 1 H); 8.68 (dd, 1 H);8.44 (s, 1
H); 8.41 (s, 1 H);8.40 (t, 1 H); 7.75 (dd, 1 H);7.66 (dd, 1 H);
7.54 (dd, 1 H);7.40-7.46 (m, 1 H); 4.64 (q,2 H); 1.48 (t, 3 H).MS
(ESI):[M + H].sup.+ = 462. 11.3 ##STR00090##
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-(2-fluor-
o-5-methyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.25 (s, 1 H);
9.21 (s, 1 H);9.08 (s, 1 H); 8.43 (s, 1 H);8.42 (s, 1 H); 8.40 (d,
1 H);8.04 (dd, 1 H); 7.74 (dd, 1 H);7.65 (dd, 1 H); 7.14 (dd, 1
H);6.81-6.86 (m, 1H); 4.64 (q,2 H); 2.30 (s, 3 H); 1.49 (t, 3H).MS
(ESI):[M + H].sup.+ = 408. 11.4 ##STR00091##
1-[4-(1-Ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-2-fluoro-phenyl]-3-m-tolyl--
urea .sup.1H-NMR:(DMSO, 400 MHz)9.16 (s, 1 H); 9.04 (s, 1 H);8.70
(s, 1 H); 8.39 (s, 1 H);8.37 (s, 1 H); 8.33 (d, 1 H);7.68 (dd, 1
H); 7.60 (dd, 1 H);7.28 (s, 1 H); 7.23 (d, 1 H);7.15 (t, 1 H); 6.79
(d, 1 H);4.59 (q, 2 H); 2.26 (s, 3 H);1.44 (t, 3 H).MS (ESI):[M +
H].sup.+ = 390.
Example Compound 12.1
Preparation of
1-{4-[1-(2-Methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3-(3-tr-
ifluoromethyl-phenyl)-urea
##STR00092##
[0545] In analogy to GP 5, 85 mg of
4-[1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenylamine
(Intermediate 3.7; 0.32 mmol, 1 eq.) were dissolved in 3 mL DCM and
treated with 49 .mu.L 1-isocyanato-3-trifluoromethyl-benzene (0.35
mmol, 1.1 eq.). The reaction mixture was stirred at rt overnight
upon which it was concentrated in vacuo, the residue was
partitioned between ethyl acetate and water and the aqueous phase
was re-extracted with ethyl acetate several times. The combined
organic layers were dried and concentrated in vacuo. Flash column
chromatography followed by trituration provided 64 mg of the
analytically pure target compound (0.140 mmol, 44% yield).
[0546] .sup.1H-NMR (d.sub.6-DMSO; 00 MHz): 9.10 (br. s, 2H); 9.00
(br. s, 1H); 8.34 (s, 1H); 8.33 (s, 1H); 8.01 (s, 1H); 7.73 (d,
2H); 7.64 (d, 2H); 7.58 (d, 1H); 7.49 (t, 1H); 7.29 (d, 1H); 4.72
(t, 2H); 3.77 (t, 2H); 3.17 (s, 3H);
[0547] MS (ESI): [M+H].sup.+=456.
[0548] The following example compounds 12.2 to 12.5 were prepared
from Intermediates 3.7 or 3.8, respectively, by reaction with the
respective isocyanates according to GP 5 in analogy to example
compound 12.1.
TABLE-US-00007 Example Structure Name Analytical data 12.2
##STR00093##
1-{4-[1-(2-Methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-3-pheny-
l-urea .sup.1H-NMR:(DMSO, 300 MHz)9.09 (s, 1 H); 8.87 (s, 1 H);8.71
(s, 1 H); 8.33 (s, 2 H);7.72 (d, 2 H); 7.62 (d, 2 H);7.45 (d, 2 H);
7.26 (t, 2 H);6.95 (t, 1 H); 4.72 (t, 2 H);3.77 (t, 2 H); 3.17 (s,
3 H). 12.3 ##STR00094##
1-(2-Fluoro-5-methyl-phenyl)-3-{4-[1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]-
pyridin-4-yl]-phenyl}-urea .sup.1H-NMR:(DMSO, 300 MHz)9.23 (s, 1
H); 9.10 (s, 1 H);8.51 (d, 1 H); 8.33 (s, 2 H);7.97 (dd, 1 H); 7.73
(d, 2 H);7.63 (d, 2 H); 7.08 (dd, 1 H);6.75-6.81 (m, 1 H); 4.72
(t,2 H); 3.77 (t, 2 H); 3.17 (s, 3 H).MS (ESI):[M + H].sup.+ = 420.
12.4 ##STR00095##
1-{2-Fluoro-4-[1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(3-trifluoromethyl-phenyl)-urea 1H-NMR:(DMSO, 300 MHz)9.50 (s,
1 H); 9.18 (s, 1 H);8.86 (d, 1 H); 8.42 (s, 2 H);8.36 (t, 1 H);
8.01 (s, 1 H);7.75 (dd, 1 H); 7.66 (dd, 1 H);7.53-7.61 (m, 2 H);
7.37 (d,1 H); 4.78 (t, 2 H); 3.82 (t, 2 H);3.22 (s, 3 H). 12.5
##STR00096##
1-{2-Fluoro-4-[1-(2-methoxy-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl-
}-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300
MHz)9.42 (d, 1 H); 9.32 (d, 1 H);9.14 (s, 1 H); 8.64 (dd, 1 H);8.38
(s, 2 H); 8.36 (t, 1 H);7.71 (dd, 1 H); 7.62 (dd, 1 H);7.49 (dd, 1
H); 7.35-7.42 (m, 1 H);4.73 (t, 2 H); 3.77 (t, 2 H);3.17 (s, 3
H).
Example Compound 13.1
Preparation of
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-methyl-pyridi-
n-4-yl)-urea
##STR00097##
[0550] In analogy to GP 10, 101 mg of
[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-carbamic acid
isopropenyl ester (Intermediate 4.1; 0.33 mmol, 1 eq.) were
dissolved in 2.2 mL THF and treated with 7 .mu.L
N-methylpyrrolidine (0.065 mmol, 0.2 eq.) and 35 mg
2-methyl-pyridin-4-ylamine (0.33 mmol, 1 eq.). The resulting
reaction mixture was refluxed for 7 h, concentrated in vacuo and
purified by preparative HPLC yielding 50 mg of the target compound
(0.14 mmol, 43% yield).
[0551] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.09 (s, 1H); 9.06 (s,
1H); 8.36 (s, 1H); 8.31 (s, 1H); 8.20 (d, 1H); 7.74 (d, 2H); 7.63
(d, 2H); 7.29 (s, 1); 7.23 (d, 1H); 4.18 (s, 3H); 2.37 (s, 3H).
[0552] MS (LC-MS): [M+H].sup.+=359.
[0553] The following example compounds 13.2 to 13.42 were prepared
from Intermediate 4.1 or Intermediate 4.2, respectively, by
reaction with the respective aniline in analogy to example compound
13.1 and GP 10.
TABLE-US-00008 Example Structure Name Analytical data 13.2
##STR00098##
1-(5-tert-Butyl-isoxazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-
-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300 MHz)9.53 (s, 1 H); 9.09
(s, 1 H);8.98 (s, 1 H); 8.35 (s, 1 H);8.31 (s, 1 H); 7.74 (d, 2
H);7.61 (d, 2 H); 6.49 (s, 1 H);4.18 (s, 3 H); 1.27 (s, 9 H).MS
(LC-MS):[M + H].sup.+ = 391. 13.3 ##STR00099##
1-[4-(4-Methyl-piperazin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300
MHz)9.09 (s, 1 H); 8.98 (s, 1 H);8.94 (s, 1 H); 8.35 (s, 1 H);8.30
(s, 1 H); 7.89 (d, 1 H);7.72 (d, 2 H); 7.62 (d, 2 H);7.58 (dd, 1
H); 7.48 (d, 1 H);4.18 (s, 3 H); 2.75-2.82 (m,4 H); 2.35-2.44 (m, 4
H);2.20 (s, 3 H).MS (LC-MS):[M + H].sup.+= 466. 13.4 ##STR00100##
1-(5-tert-Butyl-2-phenyl-2H-pyrazol-3-yl)-13-[4-(1-methyl-1H-pyrazolo[3,4-
-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300 MHz)9.22 (s, 1
H); 9.08 (s, 1 H);8.44 (s, 1 H); 8.34 (s, 1 H);8.29 (s, 1 H); 7.70
(d, 2 H);7.57 (d, 2 H); 7.49-7.53 (m,4 H); 7.35-7.43 (m, 1 H);6.37
(s, 1 H); 4.18 (s, 3 H);1.26 (s, 9 H).MS (LC-MS):[M + H].sup.+ =
466. 13.5 ##STR00101##
1-[4-(4-Methyl-piperidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300
MHz)9.09 (s, 1 H); 8.95 (s, 1 H);8.94 (s, 1 H); 8.35 (s, 1 H);8.31
(s, 1 H); 7.86 (d, 1 H);7.72 (d, 2 H); 7.62 (d, 2 H);7.57 (dd, 1
H); 7.44 (d, 1 H);4.18 (s, 3 H); 2.78-2.85 (m,2 H); 2.62-2.70 (m, 2
H);1.59-1.63 (m, 2 H); 1.35-1.50 (m, 1 H); 1.15-1.29 (m,2 H); 0.92
(d, 3 H).MS (LC-MS):[M + H].sup.+ = 509. 13.6 ##STR00102##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[4-(4-m-
ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.47 (s, 1 H); 9.13 (s, 1 H);8.82 (s, 1
H); 8.39 (s, 1 H);8.35 (s, 1 H); 8.31 (t, 1 H);7.97 (d, 1 H); 7.69
(dd, 1 H);7.59-7.63 (m, 2 H); 7.53 (dd,1 H); 4.19 (s, 3 H); 3.50
(s, 2 H);2.20-2.42 (m, 8 H); 2.12(s, 3 H).MS (LC-MS):[M + H].sup.+
= 13.7 ##STR00103##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-piperidin-1-y-
lmethyl-3-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300
MHz)9.13 (s, 1 H); 9.12 (s, 1 H);9.05 (s, 1 H); 8.40 (s, 1 H);8.35
(s, 1 H); 8.00 (d, 1 H);7.78 (d, 2 H); 7.59-7.69 (m,4 H); 4.23 (s,
3 H); 3.51 (s, 2 H);2.31-2.39 (m, 4 H); 1.47-1.57 (m, 4 H);
1.37-1.46(m, 2 H).MS (LC-MS):[M + H].sup.+ = 509. 13.8 ##STR00104##
1-[2-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1-ethyl-1H-
-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300
MHz)9.90 (s, 1 H); 9.14 (s, 1 H);8.45 (s, 1 H); 8.41 (s, 1 H);8.36
(s, 1 H); 8.20 (s, 1 H);7.80 (d, 2 H); 7.72 (d, 2 H);7.31-7.38 (m,
2 H); 4.24 (s,3 H); 2.89-2.92 (m, 4 H);2.62-2.67 (m, 4 H); 2.31
(s,3 H).MS (LC-MS):[M + H].sup.+ = 510. 13.9 ##STR00105##
1-[2-(4-Dimethylamino-piperidin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)10.04 (s, 1 H); 9.14 (s, 1 H);8.47 (s, 1
H); 8.41 (s, 1 H);8.36 (s, 1 H); 8.29 (s, 1 H);7.71-7.81 (m, 4 H);
7.30-7.37 (m, 2 H); 4.24 (s, 3 H);3.10-3.14 (m, 2 H); 2.64-2.72 (m,
2 H); 2.33-2.45 (m,1 H); 2.37 (s, 6 H); 1.82-2.00(m, 4 H).MS (LC-MS
[M + H].sup.+ = 538. 13.10 ##STR00106##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(2-pyrrolidin-1--
yl-5-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 300 MHz)9.34
(s, 1 H); 9.09 (s, 1 H);8.35 (s, 1 H); 8.31 (s, 1 H);8.03 (s, 1 H);
7.93 (d, 1 H);7.72 (d, 2 H); 7.64 (d, 2 H);7.28 (dd, 1 H); 7.05 (d,
1 H);4.19 (s, 3 H); 3.19-3.23 (m,4 H); 1.88-1.93 (m, 4 H). 13.11
##STR00107##
1-(2-Dimethylamino-5-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3-
,4-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300 MHz)9.74 (s,
1 H); 9.09 (s, 1 H);8.53 (s, 1 H); 8.50 (d, 1 H);8.36 (s, 1 H);
8.31 (s, 1 H);7.74 (d, 2 H); 7.66 (d, 2 H);7.32 (d, 1 H); 7.27 (dd,
1 H);4.19 (s, 3 H); 2.66 (s, 6 H). 13.12 ##STR00108##
1-[2-(3-Dimethylamino-pyrrolidin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1--
methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.40 (s, 1 H); 9.12 (s, 1 H);8.39 (s, 1
H); 8.34 (s, 1 H);8.16 (HCO.sub.2H signal); 8.06 (s, 1 H);7.92 (d,
1 H); 7.75 (d, 2 H);7.68 (d, 2 H); 7.32 (dd, 1 H);7.07 (d, 1 H);
4.22 (s, 3 H);3.18-3.47 (m, 4 H); 2.76-2.84 (m, 1 H); 2.10-2.19(m,
1 H); 1.76-1.85 (m, 1 H).MS (ESI-MS):[M + H].sup.+ = 524. 13.13
##STR00109##
1-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-5-trifluoromethyl-phenyl}-3-[-
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)10.07 (s, 1 H); 9.12 (s, 1 H);9.03 (s, 1
H); 8.53 (d, 1 H);8.40 (s, 1 H); 8.35 (HCO.sub.2Hsignal); 8.31 (s,
1 H); 7.73-7.78 (m, 4 H); 7.41 (d, 1 H);7.31 (dd, 1 H); 4.23 (s, 3
H);3.11 (t, 2 H); 2.70 (t, 2 H);2.68 [M + H].sup.+ = 512. 13.14
##STR00110##
1-{2-[(3-Dimethylamino-propyl)-methyl-amino]-5-trifluoromethyl-phenyl}-3--
[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.82 (s, 1 H); 9.10 (s, 1 H);8.53 (s, 1
H); 8.50 (d, 1 H);8.36 (s, 1 H); 8.33 (s, 1 H);7.75 (d, 2 H); 7.66
(d, 2 H);7.35 (d, 1 H); 7.27 (dd, 1 H);4.19 (s, 3 H); 2.91 (t, 2
H);2.64 (s, 3 H); 2.16 (t, 2 H);2.02 (s, 6 H); 1.53 (quint., 2
H).[M + H].sup.+ = 526. 13.15 ##STR00111##
1-[2-(3-Dimethylamino-piperidin-1-yl)-5-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea MS (ESI-MS):[M +
H].sup.+ = 538. 13.16 ##STR00112##
1-[4-(4-Methanesulfonyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-
-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.12 (s, 1 H); 9.10 (s, 1 H);8.95 (s, 1
H); 8.36 (s, 1 H);8.31 (s, 1 H); 7.95 (s, 1 H);7.73 (d, 2 H);
7.55-7.65 (m,4 H); 4.19 (s, 3 H); 3.55 (s, 2 H);3.05-3.15 (m, 4 H);
2.85(s, 3 H); 2.40-2.50 (overlapwith DMSO signal; 4 H).MS (LC[M +
H].sup.+ = 588. 13.17 ##STR00113##
1-[4-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3--
[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.58 (br. s, 1 H); 9.50 (br. s, 1
H);9.09 (s, 1 H); 8.36 (s, 1 H);8.31 (s, 1 H); 8.25 (br.
s,HCO.sub.2H signal); 7.96 (d, 1 H);7.72 (d, 2 H); 7.64 (d, 2
H);7.61 (dd, 1 H); 7.57 (d, 1 H);4.19 (s, 3 H); 3.61 (higherorder
q, 2 H); 2.87-2.93 (m, signal; 2 H); 2.38 (dd, 1 H);2.17 (s, 6 H);
1.83-1.91 (m,1 H); 1.60-1.69 (m, 1 H).MS (LC-MS):[M + H].sup.+ =
538. 13.18 ##STR00114##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-morpholin-4-y-
lmethyl-3-trifluoromethyl-phenyl)-urea .sup.1H-NMR:(DMSO, 400
MHz)9.09 (br. s, 2 H); 9.01 (s, 1 H);8.36 (s, 1 H); 8.31 (s, 1
H);7.97 (d, 1 H); 7.73 (d, 2 H);7.64 (d, 2 H); 7.62 (d, 1 H);7.58
(dd, 1 H); 4.19 (s, 3 H);3.55 (t, 4 H); 3.51 (s, 2 H);2.32-2.36 (m,
4 H).MS (LC-MS):[M + H].sup.+ = 511. 13.19 ##STR00115##
1-(5-Isopropyl-2-phenyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c-
]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300 MHz)9.21 (s, 1
H); 9.08 (s, 1 H);8.46 (s, 1 H); 8.33 (s, 1 H);8.28 (s, 1 H); 7.70
(d, 2 H);7.57 (d, 2 H); 7.49-7.53 (m,4 H); 7.33-7.43 (m, 1 H);6.30
(s, 1 H); 4.18 (s, 3 H);2.88 (sept, 1 H), 1.18 (d, 6 h).MS
(LC-MS):[M + H].sup.+ = 452. 13.20 ##STR00116##
1-[4-(4-Methyl-3-oxo-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-
-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.12 (s, 1 H); 9.08 (br. s, 1 H);8.37
(br. s, 1 H); 8.31 (s,1 H); 7.97 (s, 1 H); 7.73 (d, 2 H);7.64 (d, 2
H); 7.57-7.62(m, 2 H); 4.19 (s, 3 H); 3.58(s, 2 H); 3.23 (t, 2 H);
2.97 (s,2 H); 2.79 (s, 3 H); 2.60 (t, 2 H).MS (LC-MS):[M + H].sup.+
= 438. 13.21 ##STR00117##
1-[4-(4-Methyl-[1,4]diazepan-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(-
1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.79 (br. s, 3 H); 9.70 (br. s, 1
H);9.08 (s, 1 H); 8.35 (s, 1 H);8.31 (s, 1 H); 7.97 (d, 1
H);7.60-7.73 (m, 5 H); 4.18(s, 3 H); 3.65 (s, 2 H); 3.37-3.43 (m, 2
H); 2.66-2.70 (m,2 H); 2.58-2.64 (m, 4 H);2.32 (s, 3 H); 1.72
(quint., 2 H) 13.22 ##STR00118##
1-[4-(4-Methyl-piperazine-1-carbonyl)-3-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.34 (br. s, 1 H); 9.18 (br. s, 1
H);9.14 (s, 1 H); 8.41 (s, 1 H);8.36 (s, 1 H); 8.08 (d, 1 H);7.79
(d, 2 H); 7.67-7.71(m, 3 H); 7.37 (d, 1 H); 4.23(s, 3 H); 3.55-3.71
(m, 2 H);3.05-3.20 (m, 2 H); 2.13-2.46 (m, 4 H); 2.20 (s, 3 H).
13.23 ##STR00119##
1-(4-Dimethylamino-methyl-3-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 300
MHz)9.15 (br. s, 1 H); 9.14 (s, 1 H);9.08 (s, 1 H); 8.40 (s, 1
H);8.36 (s, 1 H); 7.99 (s, 1 H);7.78 (d, 2 H); 7.68 (d, 2 H);7.63
(m, 2 H); 4.23 (s, 3 H);3.48 (s, 2 H); 2.19 (s, 6 H).MS (LC-MS):[M
+ H].sup.+ = 469. 13.24 ##STR00120##
1-[4-(4-Methyl-piperidin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(1-me-
thyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.14 (br. s, 2 H); 9.08 (s, 1 H);8.40
(s, 1 H); 8.36 (s, 1 H);7.99 (d, 1 H); 7.78 (d, 2 H);7.68 (d, 2 H);
7.59-7.68(m, 2 H); 4.23 (s, 3 H); 3.52(s, 2 H); 2.73-2.79 (m, 2
H);1.92-2.01 (m, 2 H); 1.55-1.62 (m, 2 H); 1.30-1.43 (m,1 H);
1.09-1.22 (m, [M + H].sup.+ = 523. 13.25 ##STR00121##
(S)-1-[4-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3trifluoromethyl-phenyl]-
-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.41 (br. s,1 H); 9.33 (br. s, 1 H);9.09
(s, 1 H); 8.36 (s, 1 H);8.31 (s, 1 H); 8.19 (br. s,HCO.sub.2H
signal); 7.95 (d, 1 H);7.72 (d, 2 H); 7.64 (d, 2 H);7.56-7.61 (m, 2
H); 4.19 (s,3 H); 3.61 (higherorder q, 2 H);2.87-2.93 (m, 1 H);
2.61(dd, 1 H); 2.45-.55(overlap with DMSOsignal; 2 H); 2.36(dd, 1
H); 2.13 (s, 6 H); 1.82-1.90 (m, 1 H); 1.59-1.68 (m,1 H).MS
(LC-MS):[M + H].sup.+ = 538. 13.26 ##STR00122##
1-[4-(4-Cyclopropylmethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenyl]-
-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.25 (s, 1 H); 9.16 (s, 1 H);9.09 (s, 1
H); 8.35 (s, 1 H);8.31 (s, 1 H); 7.96 (d, 1 H);7.73 (d, 2 H); 7.64
(d, 2 H);7.56-7.61 (m, 2 H); 4.18 (s,3 H); 3.51 (s, 2 H);
2.31-2.51(m, 8 H; overlap with DMSOsignal); 2.19 (d, 2 H); 0.74 MS
(LC-MS):[M + H].sup.+ = 564. 13.27 ##STR00123##
1-[4-(4-Hydroxy-piperidin-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.09 (s, 1 H); 9.08 (s, 1 H);9.01 (s, 1
H); 8.36 (s, 1 H);8.31 (s, 1 H); 8.11 (s, 1 H);7.95 (d, 1 H); 7.73
(d, 2 H);7.64 (d, 2 H); 7.55-7.61 (m,2 H); 4.52 (br., 1 H); 4.19
(s,3 H); 3.48 (s, 2 H); 3.40-3.46(m, 1 H); 2.59-2.65 (m, 2 H);2.04
(t, 2 H); 1.65-1.71 (m,2 H); 1.32-1.41 (m, 2 H).MS (LC-MS):[M +
HCO.sub.2H].sup.+ = 569. 13.28 ##STR00124##
1-{4-[(3-Dimethylamino-propyl)-methyl-amino]-3-trifluoromethyl-phenyl}-3--
[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea MS
(LC-MS):[M + H].sup.+ = 526. 13.29 ##STR00125##
[1-(4-{3-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-ureido}-2-t-
rifluoromethyl-phenyl)-piperidin-4-yl]-carbamic acidtert-butyl
ester MS (LC-MS):[M + H].sup.+ = 610. 13.30 ##STR00126##
1-[4-((R)-3-Dimethylamino-pyrrolidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-
-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.13 (s, 1 H); 9.09 (s, 1 H);9.03 (s, 1
H); 8.40 (s, 1 H);8.36 (s, 1 H); 8.19 (s, 1 H;HCO.sub.2H signal);
7.88 (d, 2 H);7.76 (d, 2 H); 7.67 (d, 2 H);7.57 (dd, 1 H); 7.30 (d,
1 H);4.24 (2, 3); 3.09-3.23 (m, 4 H);2.88 (quint., 1 H); 2.22 (s,6
H); 2.03-2.13 (m, 1 H);1.73-1.85 (m, 1 H).MS (LC-MS):[M + H].sup.+
= 524. 13.31 ##STR00127##
1-[4-((S)-3-Dimethylamino-pyrrolidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-
-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 300 MHz)9.24 (s, 1 H); 9.19 (s, 1 H);9.13 (s, 1
H); 8.40 (s, 1 H);8.36 (s, 1 H); 8.23 (s, 1 H;HCO.sub.2H signal);
7.89 (d, 2 H);7.76 (d, 2 H); 7.68 (d, 2 H);7.59 (dd, 1 H); 7.32 (d,
1 H);4.24 (s, 3 ); 3.08-3.27 (m, 4 H);2.96 (quint., 1 H); 2.26 (s,6
H); 2.03-2.14 (m, 1 H);1.75-1.87 (m, 1 H).MS (LC-MS):MS (LC-MS):[M
+ H].sup.+ = 524. 13.32 ##STR00128##
4-(4-{3-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-ureido}-2-tr-
ifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl
ester MS (LC-MS):[M + H].sup.+ = 610. 13.33 ##STR00129##
1-{4-[Methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenyl}-3-
-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea MS
(LC-MS):[M + H].sup.+ = 538. 13.34 ##STR00130##
1-[4-(1-Methyl-piperidin-4-ylamino)-3-trifluoromethyl-phenyl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO,
400 MHz)9.23 (s, 1 H); 9.08 (s, 1 H);9.00 (s, 1 H); 8.35 (s, 1
H);8.31 (s, 1 H); 8.20 (HCO.sub.2H, s,1 H); 7.70 (d, 2 H); 7.69 (d,
1 H);7.63 (d, 2 H); 7.41 (dd, 1 H);7.87 (d, 1 H); 4.33 (d, 1
H);4.18 (s, 3 H); 2.75-2.83(m, 2 H); 2.22-2.29 (m, 2 H);2.26 (s, 3
H); 1.85-1.93 (m,2 H); 1.46-1.56 (m, 2 H).MS (LC-MS):[M + H].sup.+
= 524. 13.35 ##STR00131##
1-[4-(1-Methyl-piperidin-4-yloxy)-3-trifluoromethyl-phenyl]-3-[4-(1-methy-
l-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO,
400 MHz)9.27 (s, 1 H); 9.10 (s, 1 H);9.08 (s, 1 H); 8.35 (s, 1
H);8.31 (s, 1 H); 8.19 (HCO.sub.2H, s,1 H); 7.83 (d, 1 H); 7.71 (d,
2 H);7.64 (d, 2 H); 7.56 (dd, 1 H);7.23 (d, 1 H); 4.50-4.56(m, 1
H); 4.18 (s, 3 H); 2.56 -2.63 (m, 2 H); 2.31-2.41 (m,2 H); 2.23 (s,
3 H); 1.87-1.94(m, 2 H); 1.64-1.72 (m, 2 H).MS (LC-MS):[M +
HCO.sub.2H].sup.+ = 569. 13.36 ##STR00132##
1-[4-(4-Dimethylamino-piperidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-m-
ethyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
.sup.1H-NMR:(DMSO, 400 MHz)9.71 (s, 1 H); 9.66 (s, 1 H);9.08 (s, 1
H); 8.35 (s, 1 H);8.31 (s, 1 H); 8.27 (HCO.sub.2H, s, 1 H);7.91 (d,
1 H); 7.72 (d, 2 H);7.66 (d, 2 H); 7.62 (dd, 1 H);7.44 (d, 1 H);
4.18 (s, 3 H);2.88-2.92 (m, 2 H); 2.70(t, 2 H); one proton
obscuredby DMSO signal; 2.34 (s, 6 H);1.85 (br. d, 2 H);
1.47-1.56(m, 2 H).MS (LC-MS):[M + HCO.sub.2H].sup.+ = 538. 13.37
##STR00133##
1-(3-Bromo-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-
-urea .sup.1H-NMR:(DMSO, 400 MHz)9.14 (s, 1 H); 9.01 (s, 1 H);8.97
(s, 1 H); 8.40 (s, 1 H);8.36 (s, 1 H); 7.89 (dt, 1 H);7.78 (d, 2
H); 7.69 (d, 2 H);7.36 (dt, 1 H); 7.27 (t, 1 H);7.17 (dt, 1 H);
4.23 (s, 3 H).MS (LC-MS):[M + H].sup.+ = 422/424 [Br
isotopepattern). 13.38 ##STR00134##
1-(2,4-Dichloro-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-ph-
enyl]-urea MS (LC-MS):[M + H].sup.+ = 412/414 [Cl.sub.2
isotopepattern). 13.39 ##STR00135##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(3-trifluorometh-
oxy-phenyl)-urea .sup.1H-NMR:(DMSO, 400 MHz)9.13 (s, 1 H); 9.10 (s,
1 H);9.03 (s, 1 H); 8.40 (s, 1 H);8.36 (s, 1 H); 7.78 (d, 2 H);7.73
(s, 1 H); 7.67 (d, 2 H);7.43 (t, 1 H); 7.34 (d, 1 H);6.97 (d, 1 H);
4.23 (s, 3 H).MS (LC-MS):[M + H].sup.+ = 428. 13.40 ##STR00136##
1-(3-Chloro-4-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]py-
ridin-4-yl)-phenyl]-urea MS (LC-MS):[M + H].sup.+ = 446. 13.41
##STR00137##
1-(3-Isopropyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phe-
nyl]-urea .sup.1H-NMR:(DMSO, 400 MHz)9.13 (s, 1 H); 8.88 (s, 1
H);8.70 (s, 1 H); 8.40 (s, 1 H);8.35 (s, 1 H); 7.76 (d, 2 H);7.67
(d, 2 H); 7.36 (s, 1 H);7.28-7.31 (m, 1 H); 7.21 (t,1 H); 6.88 (d,
1 H); 4.23 (s, 3 H);2.86 (sept., 1 H); 1.22 (d,6 H).MS (LC-MS):[M +
H].sup.+ = 13.42 ##STR00138##
1-[3-Chloro-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-[4-(1-methyl-1H-p-
yrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea MS (LC-MS):[M + H].sup.+ =
490.
Example Compound 14.1
Preparation of
1-(4-Cyano-3-trifluoromethyl-phenyl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyr-
idin-4-yl)-phenyl]-urea
##STR00139##
[0554] Step 1
[0555] In analogy to GP 9, 500 mg
4-amino-2-trifluoromethyl-benzonitrile (1 eq.) were dissolved in
4.6 mL THF and treated with 0.35 mL N-methyl morpholine (1.2 eq.).
The resulting mixture was cooled to 4.degree. C. and treated
dropwise with 0.35 mL chloro isopropenyl formate (1.2 eq.) and
stirring was continued at rt for 5 h. The reaction mixture was
quenched with water, extracted with ethyl acetate, the combined
organic layers were dried and concentrated in vacuo. Flash column
chromatography of the residue yielded 787 mg of a 1:1 mixture of
the mono- and bis-isopropenyl carbamate of the starting aniline,
which was used in the subsequent transformation without further
purification.
Step 2
[0556] In analogy to GP 10, 100 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.45 mmol, 1 eq.) were dissolved in 3 mL THF and
treated with 9 .mu.L N-methylpyrrolidine (0.09 mmol, 0.2 eq.) and
362 mg of the product mixture of step 1. The reaction mixture was
stirred at 55.degree. C. for 5 h upon which the reaction mixture
was concentrated in vacuo and the residue was purified by
preparative HPLC to yield 103 mg of the target compound (0.24 mmol,
53% yield).
[0557] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.65 (s, 1H); 9.26 (s,
1H); 9.10 (s, 1H); 8.36 (s, 1H); 8.31 (s, 1H); 8.20 (d, 1H); 8.02
(d, 1H); 7.73-7.79 (m, 3H); 7.65 (d, 2H); 4.19 (s, 3H).
[0558] MS (ESI): [M+H].sup.+=437.
[0559] The following example compounds 14.2 to 14.6 were prepared
from the respective aniline precursors by transformation into their
respective isopropenyl carbamates in analogy to GP 9 and subsequent
reaction with Intermediate 3.1 or Intermediate 3.2, respectively,
in analogy to example compound 14.1 and GP 10.
TABLE-US-00009 Example Structure Name Analytical data 14.2
##STR00140##
1-(3-Methyl-isoxazol-5-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-
-phenyl]-urea .sup.1H-NMR:(DMSO, 300 MHz)10.12 (br. s, 1 H); 9.10
(s, 1 H); 9.05 (br. s, 1 H); 8.36 (s, 1 H); 8.31 (s, 1 H); 7.75
(d,2 H); 7.63 (d, 2 H); 5.96 (s, 1 H); 4.18 (s, 3 H); 2.14 (s, 3
H).MS (LC-MS):[M + H].sup.+ = 349. 14.3 ##STR00141##
1-(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4--
c]pyridin-4-yl)-phenyl]-urea .sup.1H-NMR:(DMSO, 400 MHz)9.09 (s, 1
H); 9.07 (s, 1 H);8.50 (s, 1 H); 8.35 (s, 1 H);8.31 (s, 1 H); 7.72
(d, 2 H);7.62 (d, 2 H); 6.05 (s, 1 H);4.18 (s, 3 H); 3.58 (s, 3
H);1.19 (s, 9 H).MS (LC-MS):[M + H].sup.+ = 404. 14.4 ##STR00142##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(6-meth-
yl-pyridin-2-yl)-urea .sup.1H-NMR:(DMSO, 400 MHz)12.1 (br. s, 1 H);
9.93 (s, 1 H);9.12 (s, 1 H); 8.47 (t, 1 H);8.41 (s, 1 H); 8.37 (s,
1 H);7.73 (dd, 1 H); 7.62-7.67(m, 2 H); 6.99 (br. d, 1 H);6.89 (d,
1 H); 4.19 (s, 3 H);2.45 (s, 3 H).MS (LC-MS):[M + H].sup.+ = 377.
14.5 ##STR00143##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-trif-
luoromethyl-pyridin-2-yl)-urea .sup.1H-NMR:(DMSO, 300
MHz)10.0-10.15 (br., 2 H); 9.13(s, 1 H); 8.53 (dd, 1 H); 8.41(s, 1
H); 8.36 (s, 1 H); 7.99 (s, 1 H); 7.73 (dd, 1 H); 7.64 (dd,1 H);
7.36 (d, 1 H); 4.19 (s, 3 H).MS (LC-MS):[M + H].sup.+ = 431. 14.6
##STR00144##
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(4-trifluorometh-
yl-oxazol-2-yl)-urea .sup.1H-NMR:(DMSO, 400 MHz)9.71 (s, 1 H); 9.09
(s, 1 H);8.46 (s, 1 H); 8.36 (s, 1 H);8.32 (s, 1 H); 7.75 (d, 2
H);7.66 (d, 2 H); 4.18 (s, 3 H).MS (LC-MS):[M + H].sup.+ = 403.
Example Compound 15.1
Preparation of
1-[2-(3-Fluoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea
##STR00145##
[0561] In analogy to GP 8, 70 mg of
4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.1; 0.31 mmol, 1 eq.) were dissolved in 3.8 mL THF
and treated with 1 mL pyridine (12.49 mmol, 40 eq.) and 106 mg of
[2-(3-fluoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-carbamic acid
phenyl ester (0.31 mmol, 1 eq.; prepared from the respective amino
pyrazole precursor by treatment with phenyl chloroformate in
analogy to procedures described in WO2007064872 or WO2005110994).
The reaction mixture was heated to 100.degree. C. for 15 min in a
Biotage Initiator microwave oven upon which the reaction mixture
was concentrated in vacuo and the residue was isolated by
trituration to yield 79 mg of the target compound (0.17 mmol, 54%
yield).
[0562] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.28 (br. s, 1H); 9.13
(s, 1H); 8.60 (br. s, 1H); 8.38 (s, 1H); 8.34 (s, 1H); 7.75 (d,
2H); 7.62 (d, 2H); 7.55-7.62 (m, 1H); 7.43-7.48 (m, 2H); 7.23-7.30
(m, 1H); 6.39 (s, 1H); 4.23 (s, 3H); 2.92 (sept., 1H); 1.26 (d,
6H).
[0563] MS (ESI): [M+H].sup.+=470.
Example Compound 15.2
Preparation of
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[2-(3-f-
luoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-urea
##STR00146##
[0565] In analogy to GP 8, 76 mg of
2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine
(Intermediate 3.2; 0.31 mmol, 1 eq.) were dissolved in 3.8 mL THF
and treated with 1 mL pyridine (12.49 mmol, 40 eq.) and 106 mg of
[2-(3-fluoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-carbamic acid
phenyl ester (0.31 mmol, 1 eq.; prepared from the respective amino
pyrazole precursor by treatment with phenyl chloroformate in
analogy to procedures described in WO2007064872 or WO2005110994).
The reaction mixture was heated to 100.degree. C. for 15 min in a
Biotage Initiator microwave oven upon which the reaction mixture
was concentrated in vacuo and the residue was isolated by
trituration to yield 77 mg of the target compound (0.16 mmol, 52%
yield).
[0566] .sup.1H-NMR (d.sub.6-DMSO; 300 MHz): 9.14-9.17 (m, 2H); 8.99
(m, 1H); 8.43 (s, 1H); 8.40 (s, 1H); 8.31 (t, 1H); 7.72 (dd, 1H);
7.57-7.65 (m, 2H); 7.42-7.48 (m, 2H); 7.29 (dt, 1H); 6.42 (s, 1H);
4.24 (s, 3H); 2.92 (sept., 1H); 1.25 (d, 6H).
[0567] MS (ESI): [M+H].sup.+=488.
[0568] The following example compounds 15.3 to 15.48 were prepared
from the respective Intermediates 3.1 or 3.2 by treatment with the
respective (hetero)aryl carbamic acid phenyl esters in analogy to
example compounds 15.1 and 15.2 and in analogy to GP 8.
TABLE-US-00010 Example Structure Name Analytical data 15.3
##STR00147##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(5-isop-
ropyl-2-phenyl-2H-pyrazol-3-yl)-urea 1H-NMR:(DMSO, 300 MHz)9.12 (s,
1 H); 9.11 (br. s, 1 H); 8.99 (br. s, 1 H); 8.38 (s, 1 H); 8.34 (s,
1 H); 8.29 (t,1 H); 7.67 (dd, 1 H); 7.59 (dd,1 H); 7.48-7.56 (m, 4
H); 7.37-7.45 (m, 1 H); 6.36 (s, 1 H);4.19 (s, 3 H); 2.86 (sept.,1
H); 1.21 (d, 6 H).MS (LC-MS):[M + H].sup.+ = 470. 15.4 ##STR00148##
1-(5-tert-Butyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-1H-pyra-
zolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.12
(s, 1 H); 9.11 (br. s, 1 H); 8.92 (br. s, 1 H); 8.38 (s, 1 H); 8.34
(s, 1 H); 8.30 (t,1 H); 7.67 (dd, 1 H); 7.59 (dd,1 H); 7.49-7.55
(m, 4 H); 7.38-7.43 (m, 1 H); 6.41 (s, 1 H);4.18 (s, 3 H); 1.26 (s,
9 H).MS (LC-MS):[M + H].sup.+ = 484. 15.5 ##STR00149##
1-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-p-
yrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.33
(br. s, 1 H); 9.13 (s, 1 H); 8.50 (br. s, 1 H); 8.39 (s, 1 H); 8.34
(s, 1 H); 7.75 (d,2 H); 7.63 (d, 2 H); 7.45 (t,1 H); 7.10-7.15 (m 2
H); 7.00(dd, 1 H); 6.42 (s, 1 H); 4.23(s, 3 H); 3.83 (s, 3 H); 1.30
(s, 9H).MS (MS-ESI):[M + H].sup.+ = 496. 15.6 ##STR00150##
1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-
-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.28 (br. s, 1
H); 9.13 (s, 1 H); 8.45 (br. s, 1 H); 8.38 (s, 1 H); 8.34 (s, 1 H);
7.75 (d,2 H); 7.62 (d, 2 H); 7.43 (d,2 H); 7.35 (d, 2 H); 6.39 (s,
1 H); 4.23 (s, 3 H); 2.39 (s, 3 H); 1.29 (s, 9 H).MS (MS-ESI):[M +
H].sup.+ = 480. 15.7 ##STR00151##
1-[5-tert-Butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.22
(br. s, 1 H); 9.13 (s, 1 H); 8.47 (br. s, 1 H); 8.38 (s, 1 H); 8.34
(s, 1 H); 7.75 (d,2 H); 7.62 (d, 2 H); 7.57-7.62(m, 2 H); 7.39 (t,
2 H); 6.41(s, 1 H); 4.23 (s, 3 H); 1.30 (s, 9 H).MS (MS-ESI):[M +
H].sup.+ = 484. 15.8 ##STR00152##
1-[5-tert-Butyl-2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.24
(br. s, 1 H); 9.13 (s, 1 H); 8.52 (br. s, 1 H); 8.39 (s, 1 H); 8.34
(s, 1 H); 7.75 (d,2 H); 7.62 (d, 2 H); 7.60 (s, 4 H); 6.42 (s, 1
H); 4.23 (s, 3 H); 1.30 (s, 9 H).MS (MS-ESI):[M + H].sup.+ = 500.
15.9 ##STR00153##
1-[5-tert-Butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.17 (s, 1 H); 9.10 (br., 1 H);8.94 (br., 1 H); 8.43 (s, 1
H);8.39 (s, 1 H); 8.33 (t, 1 H);7.72 (dd, 1 H); 7.55-7.65 (m,3 H);
7.41 (t, 2 H); 6.44 (s, 1 H); 4.23 (s, 3 H); 1.30 (s, 9 H).MS
(MS-ESI):[M + H].sup.+ = 502. 15.10 ##STR00154##
1-(5-tert-Butyl-2-pyridin-4-yl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazol-
o[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400 MHz)9.31 (s, 1
H); 9.09 (s, 1 H);8.69 (s, 1 H); 8.63 (d, 2 H);8.34 (s, 1 H); 8.30
(s, 1 H);7.71 (d, 2 H); 7.64 (d, 2 H);7.59 (d, 2 H); 6.43 (s, 1
H);4.18 (s, 3 H); 1.27 (s, 9 H).MS (LC-MS):[M + H].sup.+ = 467.
15.11 ##STR00155##
1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.16
(s, 1 H); 9.15 (br. s, 1 H); 8.90 (br. s, 1 H); 8.43 (s, 1 H); 8.39
(s, 1 H); 8.35 (t,1 H); 7.71 (dd, 1 H); 7.64 (dd,1 H); 7.35-7.43
(m, 4 H); 6.43(s, 1 H); 4.23 (s, 3 H); 2.40 (s, 3 H); 1.29 (s, 9
H).MS (ESI-MS):[M + H].sup.+ = 498. 15.12 ##STR00156##
1-[5-tert-Butyl-2-(5-fluoro-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-
-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400
MHz)9.26 (s, 1 H); 9.09 (s, 1 H);8.71 (s, 1 H); 8.65 (s, 1 H);8.59
(d, 1 H); 8.34 (s, 1 H);8.29 (s, 1 H); 7.98 (dt, 1 H);7.71 (d, 2
H); 7.57 (d, 2 H);6.43 (s, 1 H); 4.18 (s, 3 H);1.27 (s, 9 H).MS
(LC-MS):[M + H].sup.+ = 485. 15.13 ##STR00157##
1-[5-tert-Butyl-2-(5-fluoro-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[2-fluoro-4--
(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
1H-NMR:(DMSO, 400 MHz)9.13 (s, 1 H); 9.11 (br. s, 1 H); 9.02 (br.
s, 1 H); 8.70 (s, 1 H); 8.62 (d, 1 H); 8.38 (s, 1 H); 8.35 (s, 1
H); 8.22 (t,1 H); 8.00 (dt, 1 H); 7.68 (dd,1 H); 7.59 (dd, 1 H);
6.46 (s, 1 H); 4.19 (s, 1 H); 1.27 (s, 9 H).MS (LC-MS):[M +
H].sup.+ = 503. 15.14 ##STR00158##
1-[5-tert-Butyl-2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.12 (s, 1 H); 9.08 (d, 1 H);8.91 (s, 1 H); 8.38 (s, 1 H);8.34
(s, 1 H); 8.27 (t, 1 H);7.67 (dd, 1 H); 7.52-7.61 (m,5 H); 6.40 (s,
1 H); 4.19 (s, 3 H); 1.25 (s, 9 H).MS (LC-MS):[M + H].sup.+ =
518/520(Cl isotope pattern). 15.15 ##STR00159##
1-[5-tert-Butyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-me-
thyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400
MHz)9.14 (br. s, 1 H); 9.12 (s, 1 H); 8.90 (br. s, 1 H); 8.38 (s, 1
H); 8.35 (s, 1 H); 8.19 (t,1 H); 7.67 (dd, 1 H); 7.59 (dd,1 H);
7.43 (t, 1 H); 7.05-7.09(m, 2 H); 6.98 (ddd, 1 H);6.40 (s, 1 H);
4.19 (s, 3 H);3.79 (s, 3 H); 1.25 (s, 9 H).MS (MS-ESI):[M +
H].sup.+ = 514. 15.16 ##STR00160##
1-(5-Cyclopropyl-2-phenyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4-
-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.18 (s, 1 H);
9.08 (s, 1 H);8.44 (s, 1 H); 8.33 (s, 1 H);8.29 (s, 1 H); 7.77 (d,
2 H);7.57 (d, 2 H); 7.47-7.51 (m,4 H); 7.35-7.42 (m, 1 H);6.17 (s,
1 H); 4.18 (s, 3 H);1.82-1.90 (m, 1 H); 0.83-0.89 (m, 2 H);
0.64-0.70 (m, 2H).MS (LC-MS):[M + H].sup.+ = 450. 15.17
##STR00161##
1-(5-Cyclopropyl-2-phenyl-2H-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.12
(s, 1 H); 9.10 (br. s, 1 H); 8.92 (br. s, 1 H); 8.38 (s, 1 H); 8.34
(s, 1 H); 8.28 (t,1 H); 7.66 (dd, 1 H); 7.59 (dd,1 H); 7.47-7.55
(m, 4 H); 7.37-7.43 (m, 1 H); 6.20 (s, 1 H);4.19 (s, 3 H);
1.81-1.90 (m,1 H); 0.83-0.89 (m, 2 H);0.64-0.69 (m, 2 H).MS
(LC-MS):[M + H].sup.+ = 468. 15.18 ##STR00162##
1-[2-(5-Fluoro-pyridin-3-yl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl--
1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.28 (s, 1 H); 9.13 (s, 1 H);8.75 (s, 1 H); 8.71 (s, 1 H);8.65
(d, 1 H); 8.38 (s, 1 H);8.34 (s, 1 H); 8.03 (dt, 1 H);7.75 (d, 2
H); 7.62 (d, 2 H);6.43 (s, 1 H); 4.23 (s, 3 H);2.94 (sept., 1 H);
1.26 (d, 6 H).MS (LC-MS):[M + H]+ = 471. 15.19 ##STR00163##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[2-(5-f-
luoro-pyridin-3-yl)-5-isopropyl-2H-pyrazol-3-yl]-urea 1H-NMR:(DMSO,
300 MHz)9.17 (s, 1 H); 9.14 (s, 1 H);9.08 (s, 1 H); 8.74 (s, 1
H);8.67 (d, 1 H); 8.43 (s, 1 H);8.39 (s, 1 H); 8.27 (t, 1 H);8.05
(dt, 1 H); 7.73 (dd, 1 H);7.61-7.67 (m, 1 H); 6.47 (s, 1 H); 4.23
(s, 3 H); 2.93(sept., 1 H); 1.26 (d, 6 H).MS (LC-MS):[M + H]+ =
489. 15.20 ##STR00164##
1-[5-Isopropyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-
-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.20 (s, 1 H); 9.13 (s, 1 H);8.53 (s, 1 H); 8.38 (s, 1 H);8.35
(d, 1 H); 8.34 (s, 1 H);7.88 (dd, 1 H); 7.75 (d, 2 H);7.62 (d, 2
H); 7.01 (d, 1 H);6.37 (s, 1 H); 4.23 (s, 3 H);2.91 (sept., 1 H);
1.25 (d, 6 H).MS (LC-MS):[M + H]+ = 483. 15.21 ##STR00165##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[5-isop-
ropyl-2-(6-methoxy-pyridin-3-yl)-2H-pyrazol-3-yl]-urea
1H-NMR:(DMSO, 300 MHz)9.17 (s, 1 H); 9.09 (br s, 1 H);8.99 (br. s,
1 H); 8.43 (s, 1 H); 8.39 (s, 1 H); 8.31-8.36(m, 2 H); 7.88 (dd, 1
H); 7.72(dd, 2 H); 7.64 (dd, 2 H); 7.02(d, 1 H); 6.40 (s, 1 H);
4.23(s, 3 H); 3.94 (s, 3 H); 2.90(sept., 1 H); 1.25 (d, 6 H).MS
(LC-MS):[M + H]+ = 501. 15.22 ##STR00166##
1-[5-Isopropyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.32
(s, 1 H); 9.13 (s, 1 H);8.52 (s, 1 H); 8.39 (s, 1 H);8.34 (s, 1 H);
7.75 (d, 2 H);7.62 (d, 2 H); 7.45 (t, 1 H);7.10-7.15 (m, 2 H); 7.00
(dd,1 H); 6.38 (s, 1 H); 4.23 (s, 3 H); 3.82 (s, 3 H); 2.91 (sept,1
H); 1.25 (d, 6 H).MS (MS-ESI):[M + H].sup.+ = 482. 15.23
##STR00167##
1-(5-Isopropyl-2-m-tolyl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo[3,4--
c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.29 (s, 1 H);
9.13 (s, 1 H);8.52 (s, 1 H); 8.38 (s, 1 H);8.34 (s, 1 H); 7.75 (d,
2 H);7.62 (d, 2 H); 7.44 (t, 1 H);7.37 (s, 1 H); 7.34 (d, 1 H);7.25
(d, 1 H); 6.37 (s, 1 H);4.23 (s, 3 H); 2.90 (sept, 1 H);2.40 (s, 3
H); 1.25 (d, 6 H).MS (MS-ESI):[M + H]+ = 466. 15.24 ##STR00168##
1-[2-(3-Chloro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.28
(s, 1 H); 9.13 (s, 1 H);8.60 (s, 1 H); 8.39 (s, 1 H);8.34 (s, 1 H);
7.75 (d, 2 H);7.65 (s, 1 H); 7.62 (d, 2 H);7.56-7.58 (m, 2 H);
7.45-7.51 (m, 1 H); 6.38 (s, 1 H);4.23 (s, 3 H); 2.92 (sept, 1
H);1.26 (d, 6 H).MS (MS-ESI):[M + H]+ = 486. 15.25 ##STR00169##
1-[2-(4-Fluoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.23
(s, 1 H); 9.13 (s, 1 H);8.51 (s, 1 H); 8.38 (s, 1 H);8.34 (s, 1 H);
7.75 (d, 2 H);7.57-7.64 (m, 4 H); 7.39 (t,2 H); 6.36 (s, 1 H); 4.23
(s, 3 H); 2.91 (sept, 1 H); 1.25 (d, 6H).MS (MS-ESI):[M + H]+ =
470. 15.26 ##STR00170##
1-[2-(3-Chloro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-meth-
yl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400
MHz)9.12 (s, 1 H); 9.10 (d, 1 H);8.97 (s, 1 H); 8.38 (s, 1 H);8.35
(s, 1 H); 8.25 (t, 1 H);7.68 (dd, 1 H); 7.45-7.60 (m,4 H); 6.37 (s,
1 H); 4.19 (s, 3 H);2.87 (sept, 1 H); 1.21 (d, 6 H).MS (MS-ESI):[M
+ H]+ = 504/506(Cl isotope pattern). 15.27 ##STR00171##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[5-isop-
ropyl-2-(3-methoxy-phenyl)-2H-pyrazol-3-yl]-urea 1H-NMR:(DMSO, 400
MHz)9.15 (d, 1 H); 9.12 (s, 1 H);8.93 (s, 1 H); 8.38 (s, 1 H);8.35
(s, 1 H); 8.29 (t, 1 H);7.67 (dd, 1 H); 7.60 (dd, 1 H);7.42 (t, 1
H); 7.05-7.08 (m,2 H); 6.97 (m, 2 H); 6.36 (s, 1 H);4.19 (s, 3 H);
3.79 (s, 3 H);2.86 (sept, 1 H); 1.21 (d, 6H).MS (MS-ESI):[M + H]+ =
504. 15.28 ##STR00172##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[5-isop-
ropyl-2-(6-trifluoromethyl-pyridin-3-yl)-2H-pyrazol-3-yl]-urea
1H-NMR:(DMSO, 300 MHz)9.18 (s, 1 H); 9.15 (br, 2 H);9.06 (d, 1 H);
8.43 (s, 1 H);8.40 (s, 1 H); 8.32 (dd, 1 H);8.27 (t, 1 H); 8.12 (d,
1 H);7.74 (dd, 1 H); 7.64 (dd, 1 H);6.50 (s, 1 H); 4.24 (s, 3
H);2.96 (sept, 1 H); 1.27 (d, 6 H).MS (LC-MS-ESI):[M + H]+ = 539.
15.29 ##STR00173##
1-[5-Isopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(-
1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO,
300 MHz)9.31 (s, 1 H); 9.13 (s, 1 H);9.06 (d, 1 H); 8.80 (s, 1
H);8.39 (s, 1 H); 8.34 (s, 1 H);8.31 (dd, 1 H); 8.10 (d, 1 H);7.75
(d, 2 H); 7.62 (d, 2 H);6.47 (s, 1 H); 4.23 (s, 3 H);2.96 (sept, 1
H); 1.28 (d, 6 H).MS (LC-MS-ESI):[M + H]+ = 521. 15.30 ##STR00174##
1-(5-Isopropyl-2-pyridin-3-yl-2H-pyrazol-3-yl)-3-[4-(1-methyl-1H-pyrazolo-
[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.28 (s, 1
H); 9.13 (s, 1 H);8.81 (d, 1 H); 8.67 (s, 1 H);8.61 (dd, 1 H); 8.38
(s, 1 H);8.34 (s, 1 H); 8.01 (ddd, 1 H);7.75 (d, 2 H); 7.61 (d, 2
H);7.60 (dd, 1 H); 6.41 (s, 1 H);4.23 (s, 3 H); 2.93 (sept, 1
H);1.27 (d, 6 H).MS (LC-MS-ESI):[M + H]+ = 453. 15.31 ##STR00175##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(5-isop-
ropyl-2-pyridin-3-yl-2H-pyrazol-3-yl)-urea 1H-NMR:(DMSO, 300
MHz)9.17 (s, 1 H); 9.13 (s, 1 H);9.05 (s, 1 H); 8.81 (d, 1 H);8.64
(dd, 1 H); 8.43 (s, 1 H);8.39 (s, 1 H); 8.30 (t, 1 H);8.02 (ddd, 1
H); 7.72 (dd, 1 H);7.59-7.62 (m, 2 H); 6.44(s, 1 H); 4.23 (s, 3 H);
2.93(sept, 1 H); 1.26 (d, 6 H).MS (LC-MS-ESI):[M + H]+ = 471. 15.32
##STR00176##
1-[5-Isopropyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400 MHz)9.22
(s, 1 H); 9.08 (s, 1 H);8.38 (s, 1 H); 8.34 (s, 1 H);8.30 (s, 1 H);
7.70 (d, 2 H);7.57 (d, 2 H); 7.40 (d, 2 H);7.06 (d, 2 H); 6.29 (s,
1 H);4.18 (s, 3 H); 3.78 (s, 3 H);2.85 (sept, 1 H); 1.20 (d, 6
H).MS (LC-MS-ESI):[M + H]+ = 482. 15.33 ##STR00177##
1-[5-tert-Butyl-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
1H-NMR:(DMSO, 300 MHz)9.17 (s, 1 H); 9.15 (s, 1 H);9.12 (s, 1 H);
8.43 (s, 1 H);8.38 (s, 1 H); 8.31 (t, 1 H);8.09 (d, 2 H); 7.87 (d,
2 H);7.73 (dd, 1 H); 7.64 (dd, 1 H);6.51 (s, 1 H); 4.24 (s, 3
H);3.27 (s, 3 H); 1.32 (s, 9 H).MS (LC-MS-ESI):[M + H]+ = 562.
15.34 ##STR00178##
1-[5-tert-Butyl-2-(4-methanesulfonyl-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400
MHz)9.28 (s, 1 H); 9.08 (s, 1 H);8.68 (s, 1 H); 8.34 (s, 1 H);8.30
(s, 1 H); 8.03 (d, 2 H);7.83 (d, 2 H); 7.71 (d, 2 H);7.59 (d, 2 H);
6.43 (s, 1
H);4.18 (s, 3 H); 3.24 (s, 3 H);1.27 (s, 9 H).MS (LC-MS-ESI):[M +
H]+ = 544. 15.35 ##STR00179##
1-[5-tert-Butyl-2-(3,5-difluoro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-
-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO,
300 MHz)9.17 (br. s, 2 H); 9.01 (br. s, 1 H); 8.43 (s, 1 H); 8.39
(s, 1 H);8.28 (t, 1 H); 7.73 (dd, 1 H);7.64 (dd, 1 H); 7.29-7.43(m,
3 H); 6.48 (s, 1 H); 4.24(s, 3 H); 1.30 (s, 9 H).MS (LC-MS-ESI):[M
+ H]+ = 520. 15.36 ##STR00180##
1-[5-tert-Butyl-2-(3,5-difluoro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.31 (s, 1 H); 9.08 (s, 1 H);8.61 (s, 1 H); 8.34 (s, 1 H);8.30
(s, 1 H); 7.71 (d, 2 H);7.59 (d, 2 H); 7.23-7.36 (m,3 H); 6.40 (s,
1 H); 4.18 (s, 3 H); 1.26 (s, 9 H).MS (LC-MS-ESI):[M + H]+ = 502.
15.37 ##STR00181##
1-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-meth-
yl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.17 (s, 1 H); 9.15 (s, 1 H);9.07 (s, 1 H); 8.43 (s, 1 H);8.38
(s, 1 H); 8.28 (t, 1 H);8.03 (d, 2 H); 7.82 (d, 2 H);7.74 (dd, 1
H); 7.64 (dd, 1 H);6.49 (s, 1 H); 4.24 (s, 3 H);1.31 (s, 9 H).MS
(LC-MS-ESI):[M + H]+ = 509. 15.38 ##STR00182##
1-[5-tert-Butyl-2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-pyr-
azolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300 MHz)9.33
(s, 1 H); 9.13 (s, 1 H);8.70 (s, 1 H); 8.39 (s, 1 H);8.34 (s, 1 H);
8.01 (d, 2 H);7.83 (d, 2 H); 7.75 (d, 2 H);7.62 (d, 2 H); 6.46 (s,
1 H);4.22 (s, 3 H); 1.31 (s, 9 H).MS (LC-MS-ESI):[M + H]+ = 491.
15.39 ##STR00183##
1-[2-(3-Fluoro-4-methoxy-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
1H-NMR:(DMSO, 300 MHz)9.17 (s, 1 H); 9.13 (s, 1 H);8.91 (s, 1 H);
8.43 (s, 1 H);8.39 (s, 1 H); 8.33 (t, 1 H);7.72 (dd, 1 H); 7.64
(dd, 1 H);7.44-7.49 (m, 1 H); 7.29-7.38 (m, 2 H); 6.38 (s, 1
H);4.23 (s, 3 H); 3.92 (s, 3 H);2.89 (sept., 1 H); 1.24 (d, 6 H).MS
(LC-MS-ESI):[M + H]+ = 518. 15.40 ##STR00184##
1-[2-(3-Fluoro-4-methoxy-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.20 (br. s, 1 H); 9.08 (s, 1 H);8.43 (br. s, 1 H); 8.34 (s, 1
H);8.30 (s, 1 H); 7.71 (d, 2 H);7.58 (d, 2 H); 7.42 (dd, 1
H);7.25-7.33 (m, 2 H); 6.30(s, 1 H); 4.18 (s, 3 H); 3.86 (s, 3 H);
2.85 (sept., 1 H);1.20 (d, 6 H).MS (LC-MS-ESI):[M + H]+ = 500.
15.41 ##STR00185##
1-[5-tert-Butyl-2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400
MHz)9.12 (s, 1 H); 9.03 (br. s, 1 H);8.88 (br. s, 1 H); 8.38 (s, 1
H); 8.34 (s, 1 H); 8.31 (t,1 H); 7.66 (dd, 1 H); 7.53-7.61(m, 3 H);
7.48 (dt, 1 H); 7.38(t, 1 H); 6.41 (s, 1 H); 4.19 (s, 3 H); 1.24
(s, 9 H).MS (LC-MS-ESI):[M + H]+ = 502. 15.42 ##STR00186##
1-[5-tert-Butyl-2-(2-fluoro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1H-py-
razolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400 MHz)9.10
(s, 1 H); 9.08 (s, 1 H);8.44 (s, 1 H); 8.34 (s, 1 H);8.29 (s, 1 H);
7.70 (d, 2 H);7.51-7.60 (m, 4 H); 7.46 (t,1 H); 7.35 (t, 1 H); 6.38
(s, 1 H);4.19 (s, 3 H); 1.24 (s, 9 H).MS (LC-MS-ESI):[M + H]+ =
484. 15.43 ##STR00187##
1-[5-tert-Butyl-2-(3,5-dichloro-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-4-(1-
-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO,
400 MHz)9.13 (br. s, 2 H); 9.97 (br. s, 1 H);8.38 (s, 1 H); 8.35
(s, 1 H);8.20 (t, 1 H); 7.69 (dd, 1 H);7.63 (s, 3 H); 7.59 (dd, 1
H);6.43 (s, 1 H); 4.19 (s, 3 H);1.26 (s, 9 H).MS (LC-MS-ESI):[M +
H]+ = 552/554(Cl.sub.2 isotopepattern). 15.44 ##STR00188##
1-[5-tert-Butyl-2-(3,5-dichloro-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-methyl-1-
H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.28 (br. s, 1 H); 9.08 (s, 1 H);8.59 (br. s, 1 H); 8.34 (s, 1
H); 8.30 (s, 1 H); 7.71 (d, 2 H);7.56-7.64 (m, 5 H); 6.39(s, 1 H);
4.18 (s, 3 H); 1.26(s, 9 H).MS (LC-MS-ESI):[M + H]+ =
534/536(Cl.sub.2 isotopepattern). 15.45 ##STR00189##
1-[5-tert-Butyl-2-(5-fluoro-2-methyl-phenyl)-2H-pyrazol-3-yl]-3-[4-(1-met-
hyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 400
MHz)9.10 (s, 1 H); 9.08 (s, 1 H);8.34 (s, 1 H); 8.31 (s, 1 H);8.29
(s, 1 H); 7.74 (d, 2 H);7.55 (d, 2 H); 7.41-7.46 (m,1 H); 7.27-7.31
(m, 2 H);6.36 (s, 1 H); 4.18 (s, 3 H);1.96 (s, 3 H); 1.24 (s, 9
H).MS (LC-MS-ESI):[M + H]+ = 498. 15.46 ##STR00190##
1-[5-tert-Butyl-2-(5-fluoro-2-methyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea MS
(LC-MS-ESI):[M + H]+ = 516. 15.47 ##STR00191##
1-[5-tert-Butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]-3-[2-fluoro-
-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea MS
(LC-MS-ESI):[M + H]+ = 502. 15.48 ##STR00192##
1-[2-(3-Fluoro-4-methyl-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-[4-(1-meth-
yl-1H)-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea 1H-NMR:(DMSO, 300
MHz)9.22 (br. s, 1 H); 9.08 (s, 1 H);8.49 (br. s, 1 H); 8.34 (s, 1
H); 8.29 (s, 1 H); 7.71 (d, 2 H);7.57 (d, 2 H); 7.26-7.43(m, 3 H);
6.32 (s, 1 H); 4.18(s, 3 H); 2.86 (sept., 1 H);2.26 (s, 3 H); 1.20
(d, 6 H).MS (LC-MS-ESI):[M + H]+ = 484.
Example Compound 16.1
Preparation of
1-{4-[1-(2-Methanesulfonyl-ethyl)-1H-pyrazolo[3,4-c]pyridin-4-yl]-phenyl}-
-3-(3-trifluoromethyl-phenyl)-urea
##STR00193##
[0570] In analogy to GP 3, 66 mg of crude
4-bromo-1-(2-methanesulfonyl-ethyl)-1H-pyrazolo[3,4-c]pyridine
(Intermediate 2.7, 0.22 mmol, 1 eq.), 132 mg of
1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(3-trifluor-
omethyl-phenyl)-urea (0.33 mmol, 1.5 eq.) and 15 mg
Pd(PPh.sub.3).sub.4 (0.013 mmol, 6 mol %) were weighed into a
Biotage microwave vial and capped. 1.0 mL toluene, 1.0 mL EtOH and
1M aq. Na.sub.2CO.sub.3 solution (0.42 mL, 0.42 mmol, 1.9 eq.) were
subsequently added by syringe. The resulting mixture was prestirred
(10 sec) and subsequently heated to 120.degree. C. for 15 min
(fixed hold time) in a Biotage Initiator.RTM. microwave reactor.
The reaction mixture was diluted with DCM, dried and concentrated
in vacuo. Preparative HPLC purification provided 24 mg of the pure
target compound along with additional impure fractions.
[0571] 1H-NMR (DMSO, 300 MHz): 9.16 (s, 1H); 9.13 (s, 1H); 9.05 (s,
1H); 8.40 (s, 1H); 8.38 (s, 1H); 8.00 (s, 1H); 7.73 (d, 2H); 7.65
(d, 2H); 7.58 (d, 1H); 7.49 (t, 1H); 7.29 (d, 1H); 4.98 (t, 2H);
3.81 (t, 2H); 2.95 (s, 3H).
[0572] MS (LC-MS): [M+H].sup.+=504.
Example Compound 16.2
Preparation of
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[5-isop-
ropyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-yl]-urea
##STR00194##
[0574] In an adaptation of GP 8, 130 mg of
[2-fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-carbamic
acid phenyl ester (Intermediate 5.1; 0.36 mmol, 1.1 eq.) and 69 mg
of 5-isopropyl-2-(4-methoxy-phenyl)-2H-pyrazol-3-ylamine (0.3 mmol,
1 eq.) were dissolved in 4 mL THF and treated with 0.97 mL pyridine
(12 mmol, 40 eq.). The reaction mixture was heated to 120.degree.
C. for 45 min in a Biotage Initiator microwave oven upon which the
reaction mixture was concentrated in vacuo and the residue was
isolated by trituration to yield 77 mg of the target compound (0.16
mmol, 52% yield). The reaction mixture was concentrated in vacuo
and the target compound was isolated by preparative HPLC
purification.
[0575] .sup.1H-NMR (d.sub.6-DMSO; 400 MHz): 9.12 (s, 1H); 9.11 (br.
s, 1H); 8.84 (s, 1H); 8.38 (s, 1H); 8.35 (s, 1H); 8.31 (t, 1H);
7.67 (dd, 1H); 7.59 (dd, 1H); 7.39 (d, 2H); 7.07 (d, 2H); 6.32 (s,
1H); 4.19 (s, 3H); 3.80 (s, 3H); 2.84 (sept, 1H); 1.20 (d, 6H).
[0576] MS (ESI): [M+H].sup.+=500.
[0577] The following example compounds 16.3 to 16.4 were prepared
from Intermediate 5.1 by treatment with the respective (hetero)aryl
amines in analogy to example compounds 16.2 and in analogy to GP
8.
TABLE-US-00011 Example Structure Name Analytical data 16.3
##STR00195##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-(5-isop-
ropyl-2-m-tolyl-2H-pyrazol-3-yl)-urea 1H-NMR:(DMSO, 400 MHz)9.12
(br. s, 2 H); 8.91 (s, 1 H); 8.38 (s, 1 H); 8.35 (s, 1 H); 8.29 (t,
1 H); 7.67 (dd,1 H); 7.59 (dd, 2 H); 7.40 (t,1 H); 7.32 (s, 1 H);
7.30 (d,1 H); 7.22 (d, 1 H); 6.35 (s, 1 H); 4.19 (s, 3 H); 2.86
(sept.,1 H); 2.36 (s, 3 H); 1.20 (d, 6 H).MS (LC-MS):[M + H].sup.+
= 484. 16.4 ##STR00196##
1-[2-Fluoro-4-(1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[2-(4-f-
luoro-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-urea
.sup.1H-NMR:(d.sub.6-DMSO; 400 MHz)9.12 (s, 1 H); 9.08 (br. s, 1
H); 8.90 (br. s, 1 H); 8.38 (s, 1 H); 8.35 (s, 1 H); 8.28 (t, 1
H);7.67 (dd, 1 H); 7.59 (dd,1 H); 7.51-7.57 (m, 2 H); 7.36(t, 2 H);
6.35 (s, 1 H); 4.19 (s, 3 H); 2.86 (sept, 1 H);1.20 (d, 6 H).MS
(ESI):[M + H].sup.+ = 500.
Example Compound 16.5
Preparation of
1-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-3-[4-(piperidin-4--
ylamino)-3-trifluoromethyl-phenyl]-urea
##STR00197##
[0579] 113 mg of
4-(4-{3-[4-(1-Methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-ureido}-2-tr-
ifluoro-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl
ester (Example compound 13.32; 0.19 mmol, 1 eq.) were dissolved in
1 mL DCM and treated with 0.46 mL 4N HCl/dioxane solution. The
resulting mixture was stirred at rt overnight and the precipitate
was filtered off. HPLC purification provided 66 mg (64% yield) of
the target compound (as its formate salt).
[0580] .sup.1H-NMR (DMSO, 300 MHz): 9.82 (s, 1H); 9.62 (s, 1H);
9.12 (s, 1H); 8.42 (s, 1H); 8.39 (s, 1H); 8.35 (HCO.sub.2H signal);
7.68-7.76 (m, 5H); 7.51 (dd, 1H); 6.95 (d, 1H); 4.41 (d, 1H); 4.21
(s, 3H); 3.52-3.62 (m, 2H); 3.02-3.20 (m, 3H); 2.77-2.88 (m, 2H);
1.94-2.04 (m, 2H); 1.42-1.56 (m, 2H).
[0581] MS (LC-MS): [M+H].sup.+=510.
Example Compound 16.6
Preparation of
1-[4-(4-Amino-piperidin-1-yl)-3-trifluoromethyl-phenyl]-3-[4-(1-methyl-1H-
-pyrazolo[3,4-c]pyridin-4-yl)-phenyl]-urea
##STR00198##
[0583] In analogy to Example compound 16.5, treatment of
Intermediate 13.28 with 4N HCl/dioxane at room temperature provided
after HPLC purification the desired target compound.
[0584] MS (LC-MS): [M+H].sup.+=510.
[0585] The following example compounds are accessible in analogy to
the general descriptions of this invention and/or the exemplified
procedures given above or from example compounds or intermediates
by standard transformations known to the person skilled in the
art.
##STR00199## ##STR00200## ##STR00201## ##STR00202## ##STR00203##
##STR00204## ##STR00205## ##STR00206## ##STR00207## ##STR00208##
##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213##
##STR00214## ##STR00215## ##STR00216## ##STR00217## ##STR00218##
##STR00219## ##STR00220## ##STR00221## ##STR00222## ##STR00223##
##STR00224##
Description of Biological Assays
[0586] A selection of assays to profile compounds of the present
invention is described in the following paragraphs.
Assay 1: Tie2 ELISA Assay
[0587] Cellular activity of compounds of the present invention as
inhibitors of Tie2 kinase activity was measured employing a Tie2
ELISA assay as described in the following paragraphs. Herein CHO
cell-cultures, which are stably transfected by known techniques
with Tie2 using DHFR deficiency as selection marker, are stimulated
by angiopoietin-2. The specific autophosphorylation of Tie2
receptors is quantified with a sandwich-ELISA using anti-Tie2
antibodies for catch and anti-phosphotyrosine antibodies coupled to
HRP for detection.
Materials:
[0588] 96 well tissue culture plate, sterile, Greiner [0589] 96
well FluoroNunc plate MaxiSorp Surface C, Nunc [0590] 96 well plate
polypropylene for compound dilution in DMSO [0591] CHO Tie2/DHFR
(transfected cells) [0592] PBS-; PBS++, DMSO [0593] MEM alpha
Medium with Glutamax-I without Ribonucleosides and
Deoxyribonucleosides (Gibco #32561-029) [0594] with 10% FCS after
dialysis! and 1% PenStrep [0595] Lysis buffer: 1 Tablet "Complete"
protease inhibitor [0596] 1 cap Vanadate (1 mL>40 mg/mL; working
solution 2 mM) [0597] ad 50 mL with Duschl-Puffer [0598] pH 7.6
[0599] Anti-Tie2-antibody 1:425 in Coating Buffer pH 9.6 [0600]
Stock solution: 1.275 mg/mL>working.: 3 .mu.g/mL [0601] PBST: 2
bottles PBS (10.times.)+10 ml Tween, fill up with VE-water [0602]
RotiBlock 1:10 in VE-water [0603] Anti-Phosphotyrosine
HRP-Conjugated 1:10000 in 3% TopBlock [0604] 3% TopBlock in PBST
[0605] BM Chemiluminescence ELISA Substrate (POD) [0606] solution B
1:100 solution A [0607] SF9 cell culture medium [0608] Ang2-Fc in
SF9 cell culture medium
Cell Experiment:
[0608] [0609] Dispense 5.times.10.sup.4 cells/well/98 .mu.L in 96
well tissue culture plate [0610] Incubate at 37.degree. C./5%
CO.sub.2 [0611] After 24 h add compounds according to desired
concentrations [0612] Add also to control and stimulated values
without compounds 2 .mu.L DMSO [0613] And mix for a few min at room
temperature [0614] Add 100 .mu.L Ang2-Fc to all wells except
control, which receives insect medium [0615] Incubate 20 min at
37.degree. C. [0616] Wash 3.times. with PBS++ [0617] Add 100 .mu.l
Lysis buffer/well and shake a couple of min at room temperature
[0618] Store lysates at 20.degree. C. before utilizing for the
ELISA
Performance of Sandwich-ELISA
[0618] [0619] Coat 96 well FluoroNunc Plate MaxiSorp Surface C with
anti-Tie2 mAb 1:425 in Coating buffer pH 9.6; 100 .mu.L/well
overnight at 4.degree. C. [0620] Wash 2.times. with PBST [0621]
Block plates with 250 .mu.L/well RotiBlock 1:10 in VE-water [0622]
Incubate for 2 h at room temperature or overnight at 4.degree. C.
shaking [0623] Wash 2.times. in PBST [0624] Add thawed lysates to
wells and incubate overnight shaking at 4.degree. C. [0625] Wash
2.times. with PBST [0626] Add 100 .mu.L/well anti-Phosphotyrosine
HRP-Conjugated 1:10000 in 3% TopBlock (3% TopBlock in PBST) and
incubate overnight under shaking [0627] Wash 6.times. with PBST
[0628] Add 100 .mu.L/well BM Chemiluminescence ELISA Substrate
(POD) solutions 1 und 2 (1:100) [0629] Determine luminescence with
the LumiCount. Assay 2: Tie-2-Kinase HTRF-Assay without Kinase
Preactivation
[0630] Tie2-inhibitory activity of compounds of the present
invention was quantified employing two Tie2 HTRF assay as described
in the following paragraphs.
[0631] A recombinant fusion protein of GST and the intracellular
domains of Tie-2, expressed in insect cells (Hi-5) and purified by
Glutathion-Sepharose affinity chromatography was used as kinase.
Alternatively, commercially available GST-Tie2-fusion protein
(Upstate Biotechnology, Dundee, Scotland) can be used As substrate
for the kinase reaction the biotinylated peptide
biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in amid form) was used which
can be purchased e.g. from the company Biosynthan GmbH
(Berlin-Buch, Germany). Detection of phosphorylated product is
achieved specifically by a trimeric detection complex consisting of
the phosphorylated substrate, streptavidin-XLent (SA-XLent) which
binds to biotin, and Europium Cryptate-labeled anti-phosphotyrosine
antibody PT66 which binds to phosphorylated tyrosine.
[0632] Tie-2 (3.5 ng/measurement point) was incubated for 60 min at
22.degree. C. in the presence of 10 .mu.M adenosine-tri-phosphate
(ATP) and 1 .mu.M substrate peptide
(biotin-Ahx-EPKDDAYPLYSDFG-NH.sub.2) with different concentrations
of test compounds (0 .mu.M and concentrations in the range 0.001-20
.mu.M) in 5 .mu.l assay buffer [50 mM Hepes/NaOH pH 7, 10 mM
MgCl.sub.2, 0.5 mM MnCl.sub.2, 1.0 mM dithiothreitol, 0.01% NP40,
protease inhibitor mixture ("Complete w/o EDTA" from Roche, 1
tablet per 2.5 ml), 1% (v/v) dimethylsulfoxide]. The reaction was
stopped by the addition of 5 .mu.l of an aqueous buffer (25 mM
Hepes/NaOH pH 7.5, 0.28% (w/v) bovine serum albumin) containing
EDTA (90 mM) and the HTRF (Homogeneous Time Resolved Fluorescence)
detection reagents streptavidine-XLent (0.2 .mu.M, from Cis
Biointernational, Marcoule, France) and PT66-Eu-Chelate (0.3
ng/.mu.l; a europium-chelate labelled anti-phospho-tyrosine
antibody from Perkin Elmer).
[0633] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the binding of the biotinylated phosphorylated peptide to the
streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the
amount of phosphorylated substrate peptide was evaluated by
measurement of the resonance energy transfer from the
PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the
fluorescence emissions at 620 nm and 665 nm after excitation at 350
nm was measured in a HTRF reader, e.g. a Rubystar (BMG
Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
The ratio of the emissions at 665 nm and at 622 nm was taken as the
measure for the amount of phosphorylated substrate peptide. The
data were normalised (enzyme reaction without inhibitor=0%
inhibition, all other assay components but no enzyme=100%
inhibition) and IC.sub.50 values were calculated by a 4 parameter
fit using an inhouse software.
Assay 3: Tie-2-Kinase HTRF-Assay with Kinase Preactivation
[0634] A recombinant fusion protein of GST and the intracellular
domains of Tie-2, expressed in insect cells (Hi-5) and purified by
Glutathion-Sepharose affinity chromatography was used as kinase. As
substrate for the kinase reaction the biotinylated peptide
biotin-Ahx-EPKDDAYPLYSDFG (C-terminus in amid form) was used which
can be purchased e.g. from the company Biosynthan GmbH
(Berlin-Buch, Germany).
[0635] For activation, Tie-2 was incubated at a conc. 12.5 ng/.mu.l
of for 20 min at 22.degree. C. in the presence of 250 .mu.M
adenosine-tri-phosphate (ATP) in assay buffer [50 mM Hepes/NaOH pH
7, 10 mM MgCl.sub.2, 0.5 mM MnCl.sub.2, 1.0 mM dithiothreitol,
0.01% NP40, protease inhibitor mixture ("Complete w/o EDTA" from
Roche, 1 tablet per 2.5 ml)].
[0636] For the subsequent kinase reaction, the preactivated Tie-2
(0.5 ng/measurement point) was incubated for 20 min at 22.degree.
C. in the presence of 10 .mu.M adenosine-tri-phosphate (ATP) and 1
.mu.M substrate peptide (biotin-Ahx-EPKDDAYPLYSDFG-NH.sub.2) with
different concentrations of test compounds (0 .mu.M and
concentrations in the range 0.001-20 .mu.M) in 5 .mu.l assay buffer
[50 mM Hepes/NaOH pH 7, 10 mM MgCl.sub.2, 0.5 mM MnCl.sub.2, 0.1 mM
sodium ortho-vanadate, 1.0 mM dithiothreitol, 0.01% NP40, protease
inhibitor mixture ("Complete w/o EDTA" from Roche, 1 tablet per 2.5
ml), 1% (v/v) dimethylsulfoxide]. The reaction was stopped by the
addition of 5 .mu.l of an aqueous buffer (25 mM Hepes/NaOH pH 7.5,
0.28% (w/v) bovine serum albumin) containing EDTA (90 mM) and the
HTRF (Homogeneous Time Resolved Fluorescence) detection reagents
streptavidine-XLent (0.2 .mu.M, from Cis Biointernational,
Marcoule, France) and PT66-Eu-Chelate (0.3 ng/.mu.l; a
europium-chelate labelled anti-phospho-tyrosine antibody from
Perkin Elmer).
[0637] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the binding of the biotinylated phosphorylated peptide to the
streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the
amount of phosphorylated substrate peptide was evaluated by
measurement of the resonance energy transfer from the
PT66-Eu-Chelate to the streptavidine-XLent. Therefore, the
fluorescence emissions at 620 nm and 665 nm after excitation at 350
nm was measured in a HTRF reader, e.g. a Rubystar (BMG
Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
The ratio of the emissions at 665 nm and at 622 nm was taken as the
measure for the amount of phosphorylated substrate peptide. The
data were normalised (enzyme reaction without inhibitor=0%
inhibition, all other assay components but no enzyme=100%
inhibition) and IC.sub.50 values were calculated by a 4 parameter
fit using an inhouse software.
Assay 4: InsR HTRF Assay
[0638] Inhibitory activity of compounds against the kinase activity
of the insulin receptor was quantified employing the Ins-R HTRF
assay as described in the following paragraphs.
[0639] GST-tagged recombinant kinase domain of the human insuline
receptor (Ins-R, purchase from ProQinase, Freiburg, Germany)
expressed in SF-9 cells was used as kinase. As substrate for the
kinase reaction biotinylated poly-(Glu,Tyr) (Cis biointernational,
France) was used.
[0640] Ins-R was incubated for 20 min at 22.degree. C. in the
presence of different concentrations of test compounds in 5 .mu.l
assay buffer [50 mM Hepes/NaOH pH 7, 15 mM MnCl.sub.2, 1 mM
dithiothreitol, 0.1 .mu.M sodium ortho-vanadate, 0.015% (v/v)
PEG20000, 10 .mu.M adenosine-tri-phosphate (ATP), 0.3 .mu.g/ml
substrate, 1% (v/v) dimethylsulfoxide]. The concentration of Ins-R
was adjusted depending of the activity of the enzyme lot and was
chosen appropriate to have the assay in the linear range, typical
concentrations were in the range of 10 pg/.mu.L. The reaction was
stopped by the addition of 5 .mu.l of a solution of HTRF detection
reagents (0.1 .mu.M streptavidine-XLent and 1 nM PT66-Eu-Chelate,
an europium-chelate labelled anti-phospho-tyrosine antibody from
Perkin Elmer) in an aqueous EDTA-solution (80 mM EDTA, 0.2% (w/v)
bovine serum albumin in 50 mM HEPES/NaOH pH 7.0).
[0641] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the binding of the biotinylated phosphorylated peptide to the
streptavidine-XLent and the PT66-Eu-Chelate. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the PT66-Eu-Chelate to the
streptavidine-XLent. Therefore, the fluorescence emissions at 620
nm and 665 nm after excitation at 350 nm was measured in a HTRF
reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany)
or a ViewLux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition) and IC50 values were calculated by a 4
parameter fit using an inhouse software.
Additional Assays Upstate KinaseProfiler.RTM.-Radio-Enzymatic
Filter Binding Assay:
Upstate KinaseProfiler.TM.-Radio-Enzymatic Filter Binding Assay
[0642] Compounds of the present invention are assessed for their
ability to inhibit individual members of the kinase panel. The
compounds are tested in duplicates at a final concentration of 10
.mu.M following this generic protocol. Note that the kinase buffer
composition and the substrates vary for the different kinases
included in the "Upstate KinaseProfiler.TM." panel. Kinase buffer
(2.5 .mu.L, 10.times.--containing MnCl.sub.2 when required), active
kinase (0.001-0.01 Units; 2.5 .mu.L), specific or Poly(Glu4-Tyr)
peptide (5-500 .mu.M or 0.01 mg/ml) in kinase buffer and kinase
buffer (50 .mu.M; 5 .mu.L) are mixed in an eppendorf on ice. A
Mg/ATP mix (10 .mu.L; 67.5 (or 33.75) mM MgCl.sub.2, 450 (or 225)
.mu.M ATP and 1 .mu.Ci/.mu.l [.gamma.-.sup.32P]-ATP (3000 Ci/mmol))
is added and the reaction is incubated at about 30.degree. C. for
about 10 minutes. The reaction mixture is spotted (20 .mu.L) onto a
2 cm.times.2 cm P81 (phosphocellulose, for positively charged
peptide substrates) or Whatman No. 1 (for Poly(Glu4-Tyr) peptide
substrate) paper square. The assay squares are washed 4 times, for
5 minutes each, with 0.75% phosphoric acid and washed once with
acetone for 5 minutes. The assay squares are transferred to a
scintillation vial, 5 ml scintillation cocktail are added and
.sup.32P incorporation (cpm) to the peptide substrate is quantified
with a Beckman scintillation counter. Percentage inhibition is
calculated for each reaction.
[0643] Further kinase assay protocols which may be used are given
in the document "KinaseProfiler.TM. Assay Protocols", Protocol
Guide, Fall 2004, and "KinaseProfiler.TM. Protocol Guide--Addendum
I", published by the company Upstate Ltd under
http://www.upstate.com/features/kp_protocols.asp, which is hereby
incorporated by reference in its entirety.
Biological Data
[0644] Compounds of the present invention were found to possess
enzymatic and cellular activity as inhibitors of Tie2 kinase.
Preferred compounds of the present invention inhibit Tie2 kinase
activity and cellular Tie2 autophosphorylation with IC.sub.50
values below 1 .mu.M, more preferred compounds inhibit Tie2
autophosphorylation with IC.sub.50 values below 0.5 .mu.M.
Compounds of the present invention possess inhibitory selectivity
for Tie2 kinase vs. insulin receptor kinase. Preferred compounds of
the present invention are capable of inhibiting additional specific
tyrosine kinases, the inhibition of which is of therapeutic use for
the treatment of certain oncological diseases, for example.
[0645] Selected data are given in the following table. The
IC.sub.50 values were converted to pIC.sub.50 values, i.e. -log
IC.sub.50 in molar concentration.
TABLE-US-00012 Example Tie 2 activity Tie 2 activity Selectivity
vs. No. (assay 1) (assay 2) InsR 1.2 +++ +++ >50fold 1.3 +++ +++
>50fold 1.4 +++ +++ >50fold 1.5 +++ +++ >50fold 1.9 +++
+++ >50fold 1.13 +++ +++ >50fold 3.1 +++ +++ >50fold 4.1
+++ +++ >50fold 6.1 ++ ++ >25fold 6.3 +++ +++ >50fold 6.4
+++ +++ >50fold 8.1 +++ +++ >50fold 8.2 +++ +++ >50fold
8.5 +++ +++ >50fold 8.6 +++ +++ >50fold 10.5 +++ +++
>50fold 11.1 +++ +++ >50fold 11.2 +++ +++ >50fold 11.3 +++
+++ >50fold 12.1 +++ +++ >50fold 12.3 +++ +++ >50fold 12.4
+++ +++ >50fold 12.5 +++ +++ >50fold 13.2 +++ +++ >50fold
13.4 +++ +++ >50fold 13.6 +++ +++ >50fold 13.11 +++ +++
>50fold 13.12 +++ +++ >50fold 13.13 +++ +++ >50fold 13.26
+++ +++ 14.3 +++ +++ >50fold 14.5 +++ +++ >50fold 15.1 +++
+++ >50fold 15.2 +++ +++ >50fold 15.5 +++ +++ >50fold 15.7
+++ +++ >50fold 15.10 +++ +++ >50fold 15.12 +++ +++
>50fold 15.13 +++ +++ >50fold + represents pIC.sub.50 5.0-6.0
++ represents pIC.sub.50 6.0-6.3 +++ represents pIC.sub.50 >6.3
Selectivity vs. InsR: IC.sub.50 assay 4/IC.sub.50 assay 2
General Remarks
[0646] It is believed that one skilled in the art, using the
preceding information and information available in the art, can
utilize the present invention to its fullest extent. It should be
apparent to one of ordinary skill in the art that changes and
modifications can be made to this invention without departing from
the spirit or scope of the invention as it is set forth herein. All
publications, applications and patents cited above are incorporated
herein by reference.
[0647] The topic headings set forth above and below are meant as
guidance where certain information can be found in the application,
but are not intended to be the only source in the application where
information on such topic can be found.
* * * * *
References